Cellulose sulphuric acid as a biodegradable and reusable catalyst for the Knoevenagel condensation

Article abstract of DOI:10.2478/s11532-009-0111-2

A green, mild and efficient method for Knoevenagel condensation of 3-formylchromone/2-chlroquinoline-3-carbaldehyde with active methylene compounds such as Meldrum's acid/ethyl cyanoacetate using biosupported cellulose sulphuric acid (CSA) in the solid-state by grinding under solvent-free condition has been developed. This method provides several advantages including environmental friendliness, shor t reaction times, high yields and a simple work-up procedure. Moreover, the CSA was successfully reused for four cycles without significant loss of activity. Versita Warsaw and Springer-Verlag Berlin Heidelberg.

Full text of DOI:10.2478/s11532-009-0111-2

Cent. Eur. J. Chem. • 8(1) • 2010 • 12–18
DOI: 10.2478/s11532-009-0111-2
Central European Journal of Chemistry
Cellulose sulphuric acid as a biodegradable
and reusable catalyst for the Knoevenagel
condensation
Short Communication
Kiran F. Shelke, Suryakant B. Sapkal, Kirti S. Niralwad, Bapurao B. Shingate,
Murlidhar S. Shingare*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
Aurangabad-431 004 India
Received 10 August 2009; Accepted 26 September 2009
Abstract: A green, mild and efficient method for Knoevenagel condensation of 3-formylchromone/2-chlroquinoline-3-
carbaldehyde with active methylene compounds such as Meldrum’s acid/ethyl cyanoacetate using biosupported
cellulose sulphuric acid (CSA) in the solid-state by grinding under solvent-free condition has been developed. This
method provides several advantages including environmental friendliness, short reaction times, high yields and
a simple work-up procedure. Moreover, the CSA was successfully reused for four cycles without significant loss
of activity.
Keywords: Knoevenagel reaction• Cellulose sulphuric acid• Grinding• 3-formylchromone• Meldrum’s acid
© Versita Warsaw and Springer-Verlag Berlin Heidelberg
1. Introduction
Meldrum’s
acid
(2,2-dimethyl-1,3-dioxane-4,6-
dione) is an active methylene compound having a rigid
cyclic structure with high acidity (pKa = 4.9). which
readily hydrolyzes [4]. Recently, there have been
several literature methods reported for Knoevenagel
condensations of aldehydes with Meldrum’s acid [5].
In this work we introduced the quinoline nucleus for
Knoevenagel condensation since quinoline possesses
diverse biological and physiological activities, including
anti-malarial, anti-tuberculosis, receptor antagonists
and anti-cancer [6].
The grinding method has gained increasing use in
organic synthesis. Compared with traditional methods,
many organic reactions occur more efficiently in the
solid-state than in solution and in many cases even
more selectively, because molecules in the crystals are
arranged tightly and regularly [1]. Furthermore, solid-
state reactions have many advantages: little pollution,
low cost, and simplicity in progress and handling. A
large number of organic reactions can be carried out
simply and in high yield under mild conditions by this
method [2]. Therefore, we focus on developing a novel
procedure involving a solid-state reaction performed by
grinding.
Knoevenagel condensations are useful and widely
employed reactions for carbon-carbon bond formation
in organic synthesis [3]. The Knoevenagel condensation
reactions are classically catalyzed by base in liquid-
phase systems; various catalysts are known to effect the
reaction with different aldehydes and active methylene
groups.
Compounds having
a
chromone moiety are
synthetically versatile molecules with a reactive carbonyl
group. They have considerable significance for their
biological activities [7] and for their reactivity towards
nucleophiles, which allow the syntheses of a wide variety
of heterocycles. The substrate, 3-formylchromone [4-oxo-
(4H)-1-benzopyran-3-carbaldehyde] has three active
sites: an α, β-unsaturated carbonyl group, a carbon–
carbon double bond and a formyl group. Of these, the
formyl group has the highest reactivity towards active
methylene compounds. The condensation reactions of
* E-mail: msshingare_org@rediffmail.com
12

K. F. Shelke et al.
3-formylchromone with active methylene compounds KBr discs. 1H NMR spectra were recorded with a Varian
are well known [8]. It is well known that 2,2-dimethyl-5- 300 MHz spectrometer in CDCl3 with TMS as an internal
[(4-oxo-4H-chromen-3-yl)methylene]-1,3-dioxane-4,6- standard. The preparation of cellulose sulphuric acid
diones are generally synthesized by condensation of (CSA) by the dropwise addition of chlorosulfonic acid to
3-formylchromones with Meldrum’s acid in presence DEAE cellulose (Merck) suspended in hexane has been
of alumina under microwave irradiation [9a] and carried out as previously described [12].
ethyl
3-(2-chloroquinolin-3-yl)-2-cyanoacrylates
are
synthesized by condensation of 2-chloroquinoline-3-
carbaldehydes with ethyl cyanoacetate catalyzed by DBU
(1,8-diazabicycloundec-7-ene) under sonication [9b].
Biopolymers, especially ‘cellulose’ and its
derivatives [10] have some unique properties, which
make them attractive alternatives for conventional
organic or inorganic supports for catalytic applications.
Among others, they are extremely inert, inexpensive,
biodegradable and environmentally benign which allows
various reaction conditions to be employed. Cellulose
is the most abundant renewable natural material in the
world. It has been widely studied during the past decades
because it is both biodegradable and a renewable
resource.
2.1. General procedure for Knoevenagel
condensations
A mixture of heteroaromatic aldehyde (1 mmol), active
methylene compound (1 mmol) and CSA (0.5 g)
were ground at room temperature with a mortar and
pestle. The reactions were monitored by thin layer
chromatography (TLC). After completion of reaction,
the product was extracted with dichloromethane
(2×20 mL) and the insoluble CSA directly recycled in
subsequent runs. The organic layer was washed
by brine (2×10 mL), dried over Na2SO4 and the
solvent removed by rotary evaporation under reduced
pressure. The crude product was recrystallized from
ethanol to afford pure corresponding compounds in
high yield.
Recently, several synthetically useful organic
transformations using bio-supported, biodegradable and
recyclable cellulose sulphuric acid (CSA) as a catalyst
have been reported in the literature [11].
2.2. Spectral data
Compound (Table 2, 3h): IR (KBr, cm-1): 3061, 2992,
1
1730, 1669, 1372, 1296, 797. H NMR (300 MHz,
2. Experimental procedure
CDCl3) δ (ppm) = 1.9 (6H, s, 2×CH3), 7.2-8.2 (3H,
m, aromatic), 8.6 (1H, s, olefinic), 9.6 (1H, s, C2-H of
chromone moiety). EIMS (m/z, %): = 319 [M+1].
Melting points were obtained on a melting point apparatus
with capillary tubes and are uncorrected. IR spectra were
recorded on a Perkin-Elmer FTIR Spectrophotometer using
O
O
O
O
O
O
O
+
Cellulose-SO3H
Grinding, 5-15 min
CHO
R1
O
O
R1
O
O
O
1(a-h)
2
3(a-h)
Scheme 1. Synthesis of 2,2-dimethyl-5-[(4-oxo-4H-chromen-3-yl)methylene]-1,3-dioxane-4,6-dione derivatives
CHO
CN
CN
COOEt
+
Cellulose-SO3H
N
Cl
COOEt
N
Cl
R2
Grinding, 5-10 min
R2
4(a-h)
5
6(a-h)
Scheme 2. Synthesis of ethyl 3-(2-chloroquinolin-3-yl)-2-cyanoacrylate derivatives
13
13

Cellulose sulphuric acid as a biodegradable and reusable
catalyst for the Knoevenagel condensation
HO
O
O
O
O
O
O
O
O
H
H
O
HO
H
O
O
O
O
CSA-H+
H
H
O
O
Ar
O
Ar
O
O
Ar
Ar
CSA-H
CSA-H
H
CSA-H
O
O
CSA-H+
O
CSA
O
H
O
O
H
O
O
O
Ar
H
HO
H
O
Ar
O
H
H
O
H2O
O+H2
Ar
CSA
Figure 1. Proposed reaction mechanism (Scheme 1)
Table 1. Effect of proportion of CSA for the synthesis of 2,2-dimethyl-5-[(4-oxo-4H-chromen-3-yl) methylene]-1,3-dioxane-4,6-dionea [Table 2,
entry 3a] from 1 mmol each of Meldrum’s acid and aldehyde
Entry
CSA (g)
0.1
Time (min)
Yield (%)b
1
2
3
4
5
6
15
15
10
10
10
10
84
87
89
91
93
93
0.2
0.3
0.4
0.5
0.6
aReaction condition: 1a (1 mmol), 2 (1 mmol) grinding at room temperature;
bIsolated yield.
14

K. F. Shelke et al.
Table 2. Cellulose sulphuric acid catalyzed Knoevenagel reaction by grinding at room temperature (Scheme 1)
M.P. (°C)
Time
(min)
Yield
(%)a
Literature
Entry
Aldehyde
Product
Found
[9a]
O
O
O
O
O
3a
10
93
92
87
181-183
182
O
CHO
O
O
O
O
O
O
3b
3c
5
197-199
184-186
198
186
Cl
O
Cl
CHO
O
O
O
O
O
H3C
H3C
O
O
10
CHO
O
O
O
O
O
Cl
Cl
O
O
O
3d
10
15
91
89
178-180
198-200
180
200
Cl
Cl
Cl
Cl
CHO
O
O
O
O
O
CH3
CH3
O
O
O
O
O
O
O
3e
CHO
CHO
CHO
CHO
O
O
O
O
O
O
O
O
O
O
Cl
Cl
Cl
Cl
3f
3g
3h
10
92
95
96
240-242
202-204
200-202
242
205
-
O
O
O
O
5
Br
Br
O
O
O
O
O
O
5
F
O
F
O
O
O
aIsolated yield based upon starting aldehyde.
15
15

Cellulose sulphuric acid as a biodegradable and reusable
catalyst for the Knoevenagel condensation
Table 3. Cellulose sulphuric acid catalyzed Knoevenagel reaction by grinding at room temperature (Scheme 2)
M. P. (°C)
Time
(min)
Yield
(%)a
Literature
Entry
Aldehyde
Product
Found
[9b]
CHO
Cl
CN
6a
5
91
94
89
90
89
161-163
160-162
COOEt
N
Cl
N
N
N
H3CO
H3CO
CN
H3CO
CHO
6b
6c
6d
6e
5
142-144
155-157
148-150
146-148
144-146
155-157
150-152
146-148
COOEt
CN
Cl
N
N
Cl
Cl
CHO
10
10
10
COOEt
CN
H3CO
H3C
Cl
CHO H3C
COOEt
CN
N
Cl
N
N
Cl
CHO
COOEt
CN
H3C
N
Cl
H3C
Cl
CHO
6f
6g
6h
COOEt
10
5
92
87
89
160-162
170-172
164-166
162-164
168-170
165-167
N
Cl
N
Cl
CH3
CH3
C2H5
CN
C2H5
CHO
COOEt
CN
N
Cl
N
Cl
CHO
COOEt
5
N
Cl
N
Cl
C2H5
C2H5
aIsolated yield based upon starting ssaldehyde.
Table 4. Recycling of CSA for the synthesis of 2,2-dimethyl-5-[(4-oxo-4H-chromen-3-yl)methylene]-1,3-dioxane-4,6-dionea [Table 2, entry 3a]
Entry
Cycleb
1
Fresh
93
2
First reuse
91
3
Second reuse
89
4
Third reuse
88
5
Fourth reuse
88
Yield (%)c
aReaction condition: 1a (1 mmol), 2 (1 mmol) and CSA (0.5 g) grinding at room temperature;
bReaction time 10 min;
c Isolated yield.
16

K. F. Shelke et al.
grinding, i.e., using mild reaction conditions. In this
methodology, condensation reactions were completed
in a short reaction time (5-15 min) and with excellent
yields (87-96%). Thus, this is an excellent method for
the Knoevenagel condensation.
Further investigation of the ability to recycle the
catalyst is important for potential large-scale and/
or industrial operations. Therefore, the recovery and
reusability of CSA was examined. The catalyst can
be separated and reused after extracting the desired
product. The reusability of the catalyst was investigated
in the model reaction. The results illustrated in Table
4 showed that the catalyst could be used at least four
times without significant loss of activity.
3. Results and Discussion
In continuation of our research work on Knoevenagel
condensations [9,13] and on development of the novel
synthetic methodologies [14], herein, we report a simple,
efficient and safe methodology for the Knoevenagel
condensation in the presence of CSA under grinding
condition. The synthetic route is shown in Schemes 1
and 2.
In order to optimize the reaction conditions, the
reaction of 3-formylchromone 1a with Meldrum’s acid
2 was selected as a model to investigate the effect of
varying proportions of catalyst on the yield. The best
results were obtained by carrying out the reaction with
1:1 mol ratio of 3-formylchromone: Meldrum’s acid and
0.5 g of CSA under solvent-free conditions by grinding
at room temperature. Under these conditions (Table
2, entry 3a) was obtained 93% yield within 10 min.
Encouraged by the results obtained with this model
reaction. different heteroaromatic aldehydes containing
electron-withdrawing or electron-donating compounds
were reacted with both Meldrum’s acid and ethyl
cyanoacetate. They all gave the expected products with
high yields in short reaction times.
The proposed mechanism of this reaction (Scheme 1)
is as shown in Fig. 1.
4. Conclusions
In conclusion, we have reported a new and effective
methodology for the Knoevenagel reaction via the
condensation of substituted heteroaromatic aldehydes
with active methylene compounds such as Meldrum’s
acidandethylcyanoacetateinthepresenceofCSAunder
solvent-free conditions by grinding at room temperature.
The remarkable merits offered by this methodology are
mildreactionconditions,cleanerreactions,shortreaction
times, simple work-up procedures and excellent yields.
Additionally, the CSA was successfully reused for four
cycles without significant loss of activity which makes
the reaction convenient and environmentally benign.
To determine the appropriate ratio of the CSA, we
investigated the model reaction at different proportions
including 0.1, 0.2, 0.3, 0.4, 0.5 and 0.6 g (Table 1). The
Knoevenagel product formed in 84%, 87%, 89%, 91%,
93% and 93% yield, respectively, indicating that 0.5 g of
CSA is sufficient for the condensation of 1 mmol of each
substrate pair (Table 1, entry 5).
We have developed
a newer route for the
Knoevenagel condensation of 3-formylchromone/2-
chloroquinoline-3-carbaldehyde with active methylene
compounds such as Meldrum’s acid/ethyl cyanoacetate
in presence of CSA under solvent-free condition by
grinding at room temperature (Table 2 and 3). All the
reactions were carried out at room temperature by
Acknowledgements
We gratefully acknowledge the funding support received
for this work from the University Grants Commission,
New Delhi.
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