Knoevenagel condensation of aromatic aldehydes with ethyl 4-Chloro-3-oxobutanoate in ionic liquids

Article abstract of DOI:10.1590/S0103-50532012000500006

Knoevenagel condensations of aromatic aldehydes with ethyl 4-chloro-3-oxobutanoate catalyzed by morpholine/acetic acid were carried out in ionic liquids to give ethyl 2-chloroacetyl-3-arylpropenoates in 44-84percent yield after 0.5 to 2 h at room temperature (25-28 °C). These conditions represent a greener protocol for the Knoevenagel condensation than those using refluxing benzene or toluene as solvent. Aromatic aldehydes having aryl groups 4-chlorophenyl, 4-methoxyphenyl, 2-thiofuranyl, 2-furanyl, phenyl and 3,4-methylenedioxyphenyl gave (E)/(Z) diastereomeric ratios of products from 56/44 to 85/15. The two isomers of each compound were separately isolated and characterized. The structure of the (E)-isomer of ethyl 2-chloroacetyl-3-(3',4' methylenedioxyphenyl)propenoate was determined by X-ray crystallography and an unequivocal methodology of (E)/(Z)-structural analysis by ¹³C NMR (nuclear magnetic resonance) is presented.

Full text of DOI:10.1590/S0103-50532012000500006

J. Braz. Chem. Soc., Vol. 23, No. 5, 825-830, 2012.
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Article
A
Knoevenagel Condensation of Aromatic Aldehydes with
Ethyl 4‑Chloro‑3‑oxobutanoate in Ionic Liquids
Bruno R. S. de Paula,a Dávila S. Zampieri,a Julio Zukerman-Schpector,b
Edward R. T. Tiekink,c José Augusto R. Rodriguesa and Paulo J. S. Moran*,a
aInstitute of Chemistry, University of Campinas, CP 6154, 13083-970 Campinas-SP, Brazil
bDepartment of Chemistry, Federal University of São Carlos, 13565-905 São Carlos-SP, Brazil
cDepartment of Chemistry, University of Malaya, 50603 Kuala Lampur, Malaysia
Condensações de Knoevenagel de aldeídos aromáticos com 4-cloro-3-oxobutanoato de etila
catalisadas por morfolina/ácido acético foram conduzidas em líquidos iônicos para fornecerem
2-cloroacetil-3-arilpropenoatos de etila em 44 a 84% de rendimentos após 0,5 a 2 h à temperatura
ambiente (25-28 oC). Estas condições representam um protocolo mais verde para a condensação
de Knoevenagel do que aquelas realizadas com refluxo de benzeno e tolueno, utilizados como
solventes.Aldeídos aromáticos contendo grupos arila, 4-clorofenila, 4-metoxifenila, 2-tiofuranila,
2-furanila, fenila e 3,4-metilenodioxifenila apresentaram razões diastereoméricas (E)/(Z) de 56/44 a
85/15.A estrutura do isômero-(E) do 2-cloroacetil-3-(3’,4’-metilenodioxifenil)propenoato de etila
foi determinada por difração de raio X, e uma metodologia inequívoca da análise estrutural-(E)/(Z)
por RMN de 13C (ressonância magnética nuclear) é apresentada.
Knoevenagel condensations of aromatic aldehydes with ethyl 4-chloro-3-oxobutanoate
catalyzed by morpholine/acetic acid were carried out in ionic liquids to give ethyl 2-chloroacetyl-
3-arylpropenoates in 44-84% yield after 0.5 to 2 h at room temperature (25-28 oC). These conditions
represent a greener protocol for the Knoevenagel condensation than those using refluxing benzene or
toluene as solvent. Aromatic aldehydes having aryl groups 4-chlorophenyl, 4-methoxyphenyl,
2-thiofuranyl, 2-furanyl, phenyl and 3,4-methylenedioxyphenyl gave (E)/(Z) diastereomeric ratios
of products from 56/44 to 85/15. The two isomers of each compound were separately isolated and
characterized. The structure of the (E)-isomer of ethyl 2-chloroacetyl-3-(3’,4’methylenedioxyphenyl)
propenoate was determined by X-ray crystallography and an unequivocal methodology of
(E)/(Z)-structural analysis by 13C NMR (nuclear magnetic resonance) is presented.
Keywords: Knoevenagel condensation, ethyl 4-chloro-3-oxobutanoate, ionic liquid, ethyl
(E/Z)-2-chloroacetyl-3-arylpropenoate
Introduction
A set of desired compounds for these studies are
ethyl 2-chloroacetyl-3-arylpropenoates, envisaged to be
prepared by means of a Knoevenagel condensation between
ethyl 4-chloroacetoacetate and aromatic aldehydes.
However, reports of this kind of condensation involving
halogenated ketoesters are scarce at best, and the most
reproducible method employs benzene as solvent and
refluxing in a Dean-Stark to remove water from the
reaction medium.2 Although the authors successfully
obtained the product of the condensation between ethyl
4-chloroacetoacetate and benzaldehyde in up to 58% yield,
the use of considerable amounts of a hazardous organic
solvent, high temperature and rather long reaction time
are undesirable for a reaction that would be carried out
In our studies of the bioreduction of α-haloketones and
enones,1 one of our objectives is the asymmetric synthesis of
chiral halogenated β-hydroxyesters and related compounds
by means of reduction of halogenated β-ketoesters mediated
by yeasts and bacteria. In particular, the bioreduction of
ethyl 4-chloroacetoacetate derivatives bearing C=C double
bonds at the C-2 position is a potential approach to a tandem
formation of two contiguous stereogenic centers in a highly
functionalized molecule.
*e-mail: moran@iqm.unicamp.br

826
Knoevenagel Condensation of Aromatic Aldehydes with Ethyl 4-Chloro-3-oxobutanoate in Ionic Liquids
J. Braz. Chem. Soc.
Table 1. Reaction yields for the Knoevenagel condensation between ethyl
4-chloroacetoacetate (1) and benzaldehyde (2a) in ionic liquidsa
routinely. It is interesting to notice that, to this day, these
conditions are still rather common in the literature for the
Knoevenagel condensation involving several aldehydes and
active methylene compounds.3
Due to the above inconveniences, we envisaged the use
of ionic liquids as a potential alternative to the conventional
solvents.4 In recent years, ionic liquids have been the subject
of considerable interest as an efficient solvent,5 and even as
catalyst6 for the Knoevenagel condensation. Furthermore,
we have recently reported a study of the methylenation
of several carbonyl compounds in ionic liquids, using
paraformaldehyde as the methylene source and morpholine/
acetic acid as catalyst.7
Morpholine/
Acetic acid
O
O
O
O
4 Å MS
+
O
Cl
Cl
OEt
Ionic liquid
OEt
1
2a
3a
2a
3a
Yieldd /
%
Ionic
liquid
Catalystc /
mol%
entry
Concentration /
(mol L-1)b
1
2
3
4
5
6
[bmim(PF6)]
1.0
1.0
2.0
2.0
2.0
2.0
10
20
10
20
10
20
52
60
66
61
77
55
In the present work, we present the results of
the Knoevenagel condensation between ethyl
4-chloroacetoacetate 1 and aromatic aldehydes 2a-f
catalyzed by morpholine/acetic acid carried out in ionic
liquids in presence of molecular sieves at room temperature.
[bmim(NTf2)]
aReactions were carried out on a 2 mmol scale for 1 h at 25-28 oC; b1.2
equivalent of 1 was used; cmorpholine/acetic acid (1:1); dsum of the yields
of the E and Z isomers, after column chromatography.
Results and Discussion
for 2 h instead. Moreover, from the initial amount of
[bmim(NTf2)] (7.14 g), a mass of 5.57 g of the ionic liquid
(78% of the initial amount) was recovered after four cycles
of use.
In preliminary experiments to determine the best
reaction conditions, it was undertaken reactions varying
the concentration of ethyl 4-chloroacetoacetate 1 and
aromatic aldehydes 2a, the amount of catalyst added and
the nature of the ionic liquid. Since in a previous
work,7 the best methylenation results were achieved
using [bmim(PF6)] (1-butyl-3-methylimidazolium
hexafluorophosphate) and [bmim(NTf2)] (1-butyl-
3-methylimidazolium bis(trifluoromethanesulfonyl)
imide), they were the chosen ionic liquids in this work
as the potential solvents for the condensation of 1 with
2a to afford 3a. The reaction conditions, as well as the
reaction yields, are presented in Table 1. Thus, the ionic
liquid [bmim(NTf2)] was the solvent of choice for the
condensation and 2 mol L-1 concentration of 2a and
10 mol% of the catalyst (entry 5) were chosen as best
reaction conditions.
Once established the best reaction conditions, we were
prompted to investigate whether the ionic liquid could be
reused several times. Thus, four consecutive experiments
of ionic liquid reuse in the Knoevenagel condensation
were performed using entry 5 conditions stated in Table 1.
To avoid manipulation issues that may arise when using
smaller amounts of the ionic liquid, as well as to verify if
this condensation could be carried out in a larger scale, we
were prompted to perform the reaction in a 10 mmol scale
instead of 2 mmol. The yields for these experiments are
shown in Figure 1. When working in a larger scale, even
in the first reaction, the reagent had not been completely
consumed in 1 h, and the reaction had to be carried out
Figure 1. Reaction yields for the condensation between 1 (12 mmol) and
2a (10 mmol) over four reuses of ionic liquid cycles (reaction carried out
on a 5 mL of [bmin(NTf2)], morpholine (1 mmol), acetic acid (1 mmol) and
molecular sieves (1.8 g) at 25-28 oC).
Furthermore, to compare the reaction in [bmim(NTf2)]
with the traditional protocol, reactions were also performed
in refluxing benzene and toluene, using a Dean-Stark to
remove water from the reaction medium. The reaction
conditions and yields are summarized in Table 2.Although
the reaction in benzene also furnishes 3a in a high yield,
the use of benzene (which is a known carcinogen), high

Vol. 23, No. 5, 2012
de Paula et al.
827
Table 3. Reaction time, yield and diastereomeric ratio for the Knoevenagel
temperature and extended reaction time are conditions that
render the reaction less attractive. On the other hand, an
attempt to substitute benzene for toluene was unfortunately
unsuccessful, as the reaction yield decreased considerably.
This may be due to the higher reflux temperature, which
can be responsible for degradation of reagents and/or
products. Nevertheless, the pronounced ionic liquid effect
has been suggested by Pinto et al.8 and de Oliveira et al.9
as a powerful combination capable of co-promoting the
formation and stabilization of different types of ionic
intermediates10 during this kind of condensation catalyzed
by morpholine/acetic acid.
condensation between ethyl 4-chloroacetoacetate and aromatic aldehydesa
Morpholine/
Acetic acid (10 mol%)
4 Å MS
O
O
O
O
+
Cl
Ar
Cl
O
OEt
OEt
[bmim(NTf2)]
Ar
1
2a-f
3a-f
3a-f
Reaction
time / h
Aldehyde
Diastereomeric
ratio (E:Z)c
Yieldb / %
77
O
2a
1.0
1.5
2.0
1.5
0.5
73:27
56:44
59:41
85:15
69:31
O
2b
57
67
82
84
Cl
Table 2. Reaction conditions and yields for the Knoevenagel condensation
between ethyl 4-chloroacetoacetate (1) and benzaldehyde (2a)a
O
2c
O
Temperature / Reaction time /
Yieldb /
%
O
O
O
Solvent
2d
2e
ºC
h
[bmim(NTf2)]
2nd use
3rd use
25-28
2.0
73
80
83
76
75
35
O
O
O
S
2f
1.0
44
66:34
4th use
Benzene
Toluene
80
4.0
4.0
aReactions were carried out on a 2 mmol scale at room temperature
b
(25-28 oC); sum of the yields of the E and Z isomers after column
110
chromatography; cdetermined by 1H NMR of the crude mixture.
aReactions were carried out on a 10 mmol scale; bsum of the yields of the
E and Z isomers, after column chromatography.
To extend this protocol to other aromatic aldehydes,
reactions were performed with aldehydes 2b-f. The
yields for each reaction performed in accordance with
experimental condition stated in entry 5 of Table 1, as well
as the (E/Z)-isomers ratio, are collected in Table 3.
The (E/Z)-configurations of the obtained products
were assigned based on the X-ray crystallographic
analysis of the major isomer in product 3d11 and 13C NMR
spectra data. From X-ray crystallography (Figure 2),
the (E)-configuration was established for the major 3d
isomer. The analysis also shows the chloroacetyl residue
to be approximately orthogonal to the remaining molecule
(torsion angle = –87.87(18)º).
Figure 2. The molecular structure of 3d determined by X-ray
crystallography.
In order to analyze the two isomeric structures of 3d in
greater detail, density functional theory calculations were
performed with the DFT/B3LYP/6-31G++(d,p) basis set.12
The calculations show that the (E)-isomer is 0.125 kcal mol-1
more stable than (Z)-isomer. While the chloroacetyl residue
is out of molecule plane in (E)-structure, in agreement with
the structure determined by X-ray crystallography by stark
contrast in the (Z)-isomer, it is the ester residue that now lies
approximately perpendicular to the remaining molecular
plane (Figure 3).
Figure 3. Minimum energy calculated molecular (Z)- and (E)-structures
of 3d with DFT/B3LYP/6-31G++(d,p).
analysis, the carbon atom of the CH2Cl group appears
at 49.2 ppm while the corresponding carbon atom in the
(Z)-isomer appears at 46.2 ppm. In addition, the carbon atom
When the major isomer (i.e., with the (E)-configuration)
of product 3d was subjected to the magnetic field in13C NMR

828
Knoevenagel Condensation of Aromatic Aldehydes with Ethyl 4-Chloro-3-oxobutanoate in Ionic Liquids
J. Braz. Chem. Soc.
Table 4. 13C NMR chemical shifts for the –CH2Cl, C=O keto and –C(=O)OEt carbons for the major and minor isomers (3a-f)
Major isomer (E), d / ppm
Minor isomer (Z), d / ppm
Product
CH2Cl
49.2
49.0
49.3
49.2
49.1
49.1
C=O keto
196.6
–C(=O)OEt
163.8
CH2Cl
46.0
46.2
46.2
46.2
46.3
47.0
C=O keto
188.3
–C(=O)OEt
167.0
3a
3b
3c
3d
3e
3f
196.5
163.6
188.2
166.7
197.0
164.2
188.3
167.5
196.9
164.0
188.2
167.3
195.3
164.0
187.8
166.6
195.4
164.5
189.2
166.1
of carbonyl group in the (E)-isomer appears at 196.9 ppm
while corresponding carbon atom in the (Z)-isomer appears
at 188.2 ppm. On the other hand, the carbon atom of
carboxylic group of the molecule with (Z)-configuration 3d
appears at 167.3 ppm while corresponding carbon atom in
the (E)-isomer appears at 164.0 ppm.A close analysis of the
structures readily rationalizes the downfield shifts observed
in the 13C NMR spectra, i.e., of the carboxylic carbon of
the (Z)-isomer and, the carbonyl and CH2Cl carbons of the
(E)-isomer owing to their proximity and coplanarity with
the aromatic moiety. The analysis of 13C NMR spectra data
of 3a-c and 3e-f, and comparison to that of 3d, focusing
on that anisotropic effect, allowed the assignment of the
configurations in each case (Table 4).
furfural, 2-formylthiophene and ethyl 4-chloroacetoacetate
were distilled before use. All the other reagents were used
as received.
Ionic liquids were prepared following a literature
procedure,13 using 1-butyl-3-methylimidazolium
trifluoromethanesulfonate (Aldrich) and potassium
hexafluorophosphate (Aldrich) or lithium bis(trifluoro-
methanesulfonimide) (Aldrich).
Diethyl ether, benzene and toluene were purchased
from Synth. Before use, both benzene and toluene were
dried over sodium overnight, then distilled and stored over
sodium. Diethyl ether was used as received. Intact 4 Å
molecular sieves (Aldrich) were employed.
Thin-layer chromatography (TLC) analyses
were performed with precoated aluminum sheets
(silica gel 60 Merck), and flash column chromatography
was carried out on silica (200-400 mesh, Merck).
1H NMR spectra were determined at 250 MHz (Varian
Gemini 250) or 500 MHz (INOVA 500). 13C NMR spectra
were determined at 62.5 MHz (Varian Gemini 250) or
125.7 MHz (INOVA 500). Chemical shifts are reported in
Conclusions
In summary, it was demonstrated that the Knoevenagel
condensation of ethyl 4-chloroacetoacetate with aldehydes
1a-f may be accomplished in the ionic liquid [bmim(NTf2)]
as the solvent, and 10 mol% of morpholine/acetic acid as
catalyst, to give the corresponding propenoates 3a-f in
good yields, and with the (E)-isomer generally dominant.
The reaction time of 0.5 to 2 h at room temperature and
the reuse of the ionic liquid make it a suitable protocol
as an alternative to the use of benzene or toluene at
reflux temperature. The (E)- and (Z)-3a-f were isolated,
characterized and an unequivocal methodology of
(E)/(Z)-structural analysis by 13C NMR is presented.
1
ppm relative to tetramethylsilane (TMS, d 0.00 for H) in
CDCl3.
GC-MS (gas chromatography-mass spectroscopy)
analyses were obtained on an Agilent 6890 Series GC
System and mass spectra were recorded with a
Hewlett-Packard 5973 mass selective detector (70 eV)
using a HP-5MS fused silica capillary column (crosslinked
5% phenyl ethyl siloxane, 30 m × 0.25 m ID × 0.25 µm
film thickness) and helium as a carrier gas (1 mL min-1).
The split ratio was 1:50. The injector temperature was kept
Experimental
o
o
270 C and detector at 280 C. The column temperature
was held at 60 oC for 3 min and then increase to 280 oC at
a rate of 20 oC min-1, and then kept constant for 2 min at
280 oC. 1 µL of a compound solution (1 mg mL-1) in ethyl
acetate was injected, and the retention times in minutes are
reported for each compound.
All reagents were obtained from commercial sources.
Benzaldehyde, p-anysaldehyde, piperonal and ethyl
4-chloroacetoacetate were purchased fromAldrich. Furfural
was purchased from Fisher, 4-chlorobenzaldehyde and
morpholine were purchased from Merck, 2-formylthiophene
was purchased from Avocado, and glacial acetic acid was
purchased from Synth. Benzaldehyde, p-anysaldehyde,
IR spectra were recorded on a FTIR BOMEM MB-100
from Hartmann & Braun.

Vol. 23, No. 5, 2012
de Paula et al.
829
GC-HRMS (gas chromatography high-resolution mass
spectrometry) analyses were performed on a GCT Premier
(Waters) GC-MS/TOF (time-of-flight) using a HP5-MS
column (30 m × 0.25 mm ID × 0.25 µm film thickness).
The injector temperature was kept at 260 oC and detector
at 280 oC. The column temperature was held at 100 oC for
1 min and then increase to 280 oC at a rate of 10 oC min-1.
1 µL of a compound solution (1 mg mL-1) in ethyl acetate
was injected.
aid of ethyl acetate (4 × 1 mL). The solvent was evaporated
under vacuum and the ionic liquid reloaded with the
reagents, catalyst and molecular sieves for subsequent
reaction.
After the fourth reaction, 5 mL of ethyl acetate was
added to the ionic liquid, and the organic phase was washed
with distilled water (3 × 5 mL). The organic layer was
filtered through a short basic alumina column (using ethyl
acetate as the eluent), the solvent was evaporated and the
ionic liquid was dried under reduced pressure.
Melting points (mp) were determined on a Gehaka
PF1000 or on a Gehaka PF1500.
Procedure for the Knoevenagel condensation between ethyl
4-chloroacetoacetate and benzaldehyde in benzene and
toluene
General procedure for the Knoevenagel condensation in
ionic liquids
Morpholine (17.4 mg, 0.1 mmol), glacial acetic acid
(12.0 mg, 0.2 mmol) and aldehyde (2 mmol) were added
to the ionic liquid (1 mL) in a 10 mL round-bottom
flask. The mixture was stirred for 10 min, then ethyl
4-chloroacetoacetate (395 mg, 2.4 mmol) and 4Å molecular
sieves (360 mg) were added, and the mixture was stirred at
room temperature (25-28 oC). After the reaction time, the
products were extracted with diethyl ether (3 × 5 mL), the
ether was evaporated and the (E)- and (Z)-product mixture
was isolated by column chromatography on silica gel (50 g
of silica:1 g of crude mixture) using hexane/ethyl acetate
(95%:5%) as eluent. For characterization purposes, the
(E)- and (Z)-products were further separated from each
other by column chromatography on silica gel (200 g of
silica:1 g of crude mixture) using hexane/ethyl acetate
as eluent, ranging from pure hexane to 95% hexane:5%
ethyl acetate.
Morpholine (87 mg, 1 mmol), glacial acetic acid (60 mg,
1 mmol) and benzaldehyde (1.06 g, 10 mmol) were added
to benzene or toluene (5 mL) in a 25 mL round-bottom
flask connected to a Dean-Stark apparatus. The mixture
was stirred for 10 min, and then ethyl 4-chloroacetoacetate
(1.97 g, 12 mmol) was added to reaction mixture, which
was brought to a reflux. The reaction was monitored by
TLC, and after 4 h, the reaction mixture was cooled,
diluted with diethyl ether (20 mL) and washed with
water (2 × 10 mL). The solvents were evaporated, and the
products were purified by column chromatography (on
silica gel using hexane/ethyl acetate as solvent, ranging
from pure hexane to 95% hexane:5% ethyl acetate).
Acknowledgements
Conselho Nacional de Desenvolvimento Científico e
Tecnológico (CNPq), Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP) and the Ministry of
Higher Education, Malaysia, High-Impact Research
scheme (UM.C/HIR/MOHE/SC/12) to ERTT are gratefully
acknowledged.
Procedure for the Knoevenagel condensation between ethyl
4-chloroacetoacetate and benzaldehyde in [bmim(NTf2)] -
recycle experiments
Morpholine (87 mg, 1 mmol), glacial acetic acid
(60 mg, 1 mmol) and benzaldehyde (1.06 g, 10 mmol) were
added to [bmim(NTf2)] (5 mL) in a 25 mL round-bottom
flask. The mixture was stirred for 10 min, then ethyl
4-chloroacetoacetate (1.97 g, 12 mmol) and 4Å molecular
sieves (1.80 g) were added, and the mixture was stirred at
room temperature (25-28 oC). The reaction was monitored
by TLC, and after 2 h, the products were extracted with
diethyl ether (4 × 10 mL). The ether was evaporated and
the products were purified by column chromatography (on
silica gel using hexane/ethyl acetate as solvent, ranging
from pure hexane to 95% hexane:5% ethyl acetate).
The ionic liquid was washed with 10 mL of water, then
transferred to another 25 mL round bottom flask with the
Supplementary Information
EI-MS, IR, 1H NMR, 13C NMR, EI-HRMS spectra and
spectral data of all synthetized compounds are available free
of charge at http://jbcs.sbq.org.br as PDF file.
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J. Braz. Chem. Soc.
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