Chitosan: An efficient biodegradable and recyclable green catalyst for one-pot synthesis of 3,4-dihydropyrimidinones of curcumin in aqueous media

Article abstract of DOI:10.1016/j.catcom.2012.06.017

An efficient procedure for the synthesis of curcumin 3,4- dihydropyrimidinones has been developed by simple one-pot condensation of curcumin, aromatic aldehydes and urea/thiourea in the presence of commercially available chitosan in 2% acetic acid in aqueous media at 60°C for 80-90 min. In the reaction, curcumin: a potential biologically active molecule has been used as a component of multi-component synthesis using chitosan as an efficient biodegradable and recyclable green catalyst. The resultant product curcumin 3,4-dihydropyrimidinone is formed in excellent yield (97%). The chitosan catalyst can be reused for without loss of catalytic activity.

Full text of DOI:10.1016/j.catcom.2012.06.017

Catalysis Communications 27 (2012) 38–43
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Chitosan: An efficient biodegradable and recyclable green catalyst for one-pot
synthesis of 3,4-dihydropyrimidinones of curcumin in aqueous media
a
a
Jaggi Lal a,b, , Sushil K. Gupta , Dau D. Agarwal
⁎
a
School of Studies in Chemistry, Jiwaji University, Gwalior-474 011, India
Department of Industrial Chemistry, Jiwaji University, Gwalior-474 011, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2012
Received in revised form 21 May 2012
Accepted 14 June 2012
Available online 21 June 2012
An efficient procedure for the synthesis of curcumin 3,4-dihydropyrimidinones has been developed by sim-
ple one-pot condensation of curcumin, aromatic aldehydes and urea/thiourea in the presence of commercial-
ly available chitosan in 2% acetic acid in aqueous media at 60 °C for 80–90 min. In the reaction, curcumin: a
potential biologically active molecule has been used as a component of multi-component synthesis using chi-
tosan as an efficient biodegradable and recyclable green catalyst. The resultant product curcumin 3,4-
dihydropyrimidinone is formed in excellent yield (97%). The chitosan catalyst can be reused for without
loss of catalytic activity.
Keywords:
Curcumin
Chitosan
© 2012 Elsevier B.V. All rights reserved.
Biodegradable catalyst
Curcumin 3,4-dihydropyrimidinone
Multi-component reaction
1. Introduction
In recent years, Biginelli reaction has been performed under a wide va-
riety of conditions, and several improvements for the experimental proce-
Curcumin is a naturally occurring 1,3-dicarbonyl compound isolated
as a yellow pigment from turmeric of the herb Curcuma longa rhizomes.
It is commonly used as a food colorant spice and as traditional medicine
in India and China. Literature review shows that curcumin and its deriva-
tives have various biological activities such as anti-oxidant, anti-
microbial, anti-HIV, anti-inflammatory, anti-Alzheimer's, wound healing,
anticancer as well as hydrogen-peroxide-induced oxidative stress [1–8].
In recent decade, one-pot multi-component reactions [9] (MCRs) are
considered as the most powerful tool in organic synthesis because
of the significant advantages they offer, such as the synthesis of
complex molecules from readily available building blocks, easy
workup procedure, higher yield, a single purification step and di-
versity can be achieved simply by varying reaction substrates. In
multi-component reaction at least three reaction substrates are
required. Biginelli condensation or reaction involving a ternary
cyclocondensation of substituted aldehydes, β-ketoester and urea
is the most recognized and widely employed multi-component
reaction for the preparations of dihydropyrimidinones. These
dihydropyrimidinones have been found to possess various phar-
macological activities such as anti-oxidant, anti-tubercular, anti-
bacterial as well as anti-inflammatory [10–13].
dures have been made, although, it has been traditionally catalyzed by
acids and bases [14]. Such type of reactions has been successfully cata-
lyzed by various other catalysts such as hydrotalcites etc. [15]. Looking
into the biological activities of curcumin and the resultant 3,4-
dihydropyrimidinone analogs, we describe herein the synthesis of a
new class of 3,4-dihydropyrimidinone analogs of curcumin (Table 1) in
one-pot three component cyclocondensation of curcumin 1, substituted
aromatic aldehydes 2, and urea/thiourea 3 in the presence of commer-
cially available chitosan as biodegradable and recyclable green catalyst
in 2% aqueous acetic acid solution at 60 °C.
In recent years, to minimize waste and the atom economy in the
use of raw materials, the target of science and technology has been
shifting towards more environment friendly, sustainable resources
and reusable catalyst. In this direction every contribution to the
development of new “green” techniques, whether small or large, is
important if we are to minimize the production of waste. Thus, bio-
polymers are attractive candidates in the search for such biodegrad-
able and non-toxic catalyst. Chitosan is a deacetylated product of the
naturally abundant and renewable polymer. It is easily prepared
from the treatment of inexpensive chitin with alkali [16]. Chitosan
offers a unique set of environmentally benign properties such as bio-
degradability to harmless products, non-toxicity, biocompatibility,
recyclability [17–19], physiological inertness, stability to air and
moisture, and inexpensiveness or cheapness. It can be quantitatively
recovered by adding aqueous solution of alkali, filtered and reused
without drying. It gives excellent yield of the targeted product (4).
⁎
Corresponding author at: School of Studies in Chemistry, Jiwaji University,
Gwalior-474 011, India. Tel.: +91 9039035228.
E-mail address: jaggitajagra@gmail.com (J. Lal).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.06.017

J. Lal et al. / Catalysis Communications 27 (2012) 38–43
39
Table 1
Synthesis of curcumin 3,4-dihydropyrimidinones.a
Entry
R
X
Time (min)
Yield (%)b
Mp. (°C)
1
2
3
4
5
6
7
8
9
10
C6H5
O
O
O
O
O
O
O
S
80
80
80
90
80
80
90
80
80
80
97
94
96
95
94
95
94
94
96
94
207–208
211–212
152–153
202–203
225–227
199–200
159–161
218–219
295–296
262–263
4-OCH3-C6H4
4-OH-C6H4
4-Cl-C6H4
4-HO-3-OCH3-C6H3
4-NO2-C6H4
4-CH3-C6H4
C6H5
4-HO-3-OCH3-C6H3
4-CH3-C6H4
S
S
a
Curcumin (1 mmol), aromatic aldehyde (1 mmol) and urea/thiourea (1.2 mmol) in
the presence of chitosan at 60 °C for 80–90 min.
b
Isolated yield.
Fig. 1. Effect of reaction time on product yield.
In continuation with our previous work [20], commercially available
chitosan has been utilized as a biodegradable, biopolymeric catalyst for
the synthesis of 3,4-dihydropyrimidinone analogs of curcumin. To the
best of our knowledge, chitosan has not been reported as catalyst in
multi-component synthesis in aqueous media (Scheme 1).
Table 3
Optimization of chitosan catalyst.a
Entry
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
0.5% Acetic acid in water
1% Acetic acid in water
2% Acetic acid in water
2.5% Acetic acid in water
3% Acetic acid in water
5% Acetic acid in waterc
Water
81
89
97
86
72
27
–
The present study has the following advantages:
• Using chitosan reaction has been carried out in aqueous medium,
thus making heat and mass transfer more efficient in water
medium.
• Chitosan is a naturally occurring material.
• Recyclability is more efficient (goes up to 98% recovery) as chitosan
is a biopolymer.
No catalystd
–
Solvent freec
36
a
Curcumin (1 mmol), benzaldehyde (1 mmol) and urea (1.2 mmol) in the presence/
absence of chitosan at 60 °C for 80 min.
b
Isolated yield.
Not easy to workup.
In 2% acetic acid alone (without catalyst).
c
2. Experimental
d
2.1. General remarks
1H NMR spectra were recorded on BRUKER AVANCE II 400 NMR spec-
trometer. Mass spectra were recorded on a JEOL-AccuTOF JMS-T100LC
Mass spectrometer. HPLC analysis of curcumin was carried out using Var-
ian 920 instrument with RI detector, column C18 (250 mm×4.6 mm×
5 μ), solvent system 80% CH3CN+20% H2O, flow rate 1 mL/min. HPLC
purity was reported by area%.
2.2. Isolation of curcumin
Took 10 g turmeric (Curcuma longa) powder in a 100 mL beaker
and to this distilled water was added to wet turmeric powder. To
this potassium hydroxide solution was added till its pH reaches to
10–11. After stirring for about 15 min the contents were filtered.
Scheme 1. Synthesis of curcumin 3,4-dihydropyrimidinones.
Table 2
Effect of molecular weight of chitosan on product yield.a
Entry Type of chitosanb
Time
(min.) (°C)
Temp. Yield Recovery
(%)c of catalyst
(%)
1
2
High molecular weight
(310>375 kDa, >75% DDA, viscosity
800–2000 cps)
Medium molecular weight
(190–310 kDa, 75–85% DDA, viscosity
200–800 cps)
Low molecular weight (50–190 kDa, 90
75–85% DDA, viscosity 20–200 cps)
80
90
60
60
60
97
92
86
98
91
86
3
a
Curcumin (1 mmol), benzaldehyde (1 mmol) and urea (1.2 mmol) in the presence
of chitosan at 60 °C for 80–90 min.
b
Purchased from Sigma Aldrich.
Isolated yield.
c
Fig. 2. Recyclability and reusability of the catalyst.

40
J. Lal et al. / Catalysis Communications 27 (2012) 38–43
2.3. Synthesis of 3,4-dihyrdopyrimidinone analogs of curcumin under
aqueous media
In a 100 mL round bottom flask, chitosan catalyst (0.08 g) was
dissolved in 10 mL 2% aqueous acetic acid solution and to it cur-
cumin 1 (1 mmol), aromatic aldehydes 2 (1 mmol) and urea/thio-
urea 3 (1.2 mmol) were added and heated at 60 °C on a magnetic
stirrer for 80–90 min (based on substituted aldehydes). The reaction
was monitored by TLC using acetone/hexane (4:6) ratio as eluent.
After completion of the reaction, contents were filtered to get syn-
thesized product 4 (Table 1). The residue thus obtained was purified
by silica gel column chromatography (acetone/hexane, v:v=4:6) to
afford their respective pure title products and filtrate was treated
with 0.4 mol/L NaOH solution to recover the chitosan catalyst. The
catalyst was washed with water and reused.
Fig. 3. Reuse of chitosan catalyst.
3. Results and discussion
Few drops of acetic acid were added to the filtrate until the yellow
color precipitate persists and its pH was maintained between 4 and
6 for precipitation of curcumin; the precipitate was filtered using
Whatman filter paper No. 1, and the residue was washed with dis-
tilled water until the smell of acetic acid was removed. The product
was dried at room temperature and recrystallized from acetone to
get solid product. The isolated curcumin was found to have 99.86%
purity using HPLC analysis.
In the present communication, curcumin 3,4-dihydropyrimidinones
in 2% aqueous acetic acid solution have been synthesized. After the suc-
cess of the reaction, the effect of various solvents viz. methanol, ethanol,
propanol, acetonitrile, toluene, DMF, DMSO, mixture of ethanol and
DMF, ethanol and DMSO were studied. The yield of the desired product
was very poor in all the organic solvents studied up to 10 h. This observa-
tion can be attributed to the insolubility of chitosan catalyst in the organic
solvents. Chitosan is soluble in minimum 1% aqueous acetic acid solution.
Fig. 4. 1H NMR spectra of chitosan catalyst before applying for the reaction.

J. Lal et al. / Catalysis Communications 27 (2012) 38–43
41
Fig. 5. 1H NMR spectra of chitosan catalyst after recycling.
Substituted aromatic aldehydes containing both electron donating and
withdrawing groups afforded high yields of the desired products with
high purity, (Table 1). This shows that substitution of benzaldehyde has
no significant effect. Similar results were observed for the synthesis of
3,4-dihydropyrimidinones of curcumin using thiourea. Catalyst was re-
covered from the filtrate after completion of the reaction.
3.1.3. Optimization of chitosan catalyst
For the synthesis of curcumin 3,4-dihydropyrimidinones, curcumin
(1 mmol), benzaldehyde (1 mmol) and urea (1.2 mmol) were used
using amount of acetic acid (0.5, 1.0, 2.0, 2.5, 3.0 and 5.0 mL) respective-
ly in 100 mL aqueous medium. Best yield (97%) was obtained in 2%
aqueous acetic acid solution. It was observed that increase in acetic
acid concentration from 2 to 5% resulted in viscous gel formation thus
retarding the yield of the product (Table 3, entry 6). No final product
was formed in the presence of only 2% acetic acid (without catalyst),
Table 3, entry 8.
3.1. Catalytic studies
3.1.1. Effect of molecular weight of chitosan on product yield
In order to test the appropriate molecular weight of chitosan cat-
alyst, three types of chitosan were used for the study and it was con-
cluded that chitosan of high molecular weight gives maximum yield
of the desired product. The yield decreases with decrease in molecu-
lar weight of chitosan (Table 2).
3.1.4. Substrate scope study
Chitosan 0.08 g in 2% aqueous acetic acid solution was used for the
condensation of curcumin (1 mmol), aromatic aldehyde (1 mmol)
and urea/thiourea (1.2 mmol) (Table 1). Seven substituted aromatic
aldehydes were tested in the reaction; the yield of the condensation
products is about 97% indicating that 0.08 g chitosan in 2% aqueous
acetic acid solution has a high level of activity for the reaction.
3.1.2. Effect of reaction time
In order to study the effect of reaction time on the yield of the
product, the reaction was studied at different times (20, 30, 40, 50,
60, 70, 75, 80, 85 and 90 min), for the model reaction between cur-
cumin (1 mmol), benzaldehyde (1 mmol) and urea (1.2 mmol) in
the presence of 0.08 g chitosan in 2% aqueous acetic acid solution
(10 mL) at 60 °C. It was observed that there is a sharp increase in
the yield from 70 to 80 min. After 80 min the yield of the product
reached its maximum level and no further enhancement was
observed if a longer reaction time was applied. So, reaction time
80 min was chosen as the optimum reaction time for the reaction
(Fig. 1).
3.2. Recyclability and reusability of chitosan catalyst
The recyclability and reusability of the chitosan catalyst were test-
ed upon the reaction of curcumin (1 mmol), benzaldehyde (1 mmol)
and urea (1.2 mmol) employing 0.08 g chitosan catalyst in 2% aque-
ous acetic acid solution (Fig. 2), chitosan can be recovered after com-
pletion of the reaction from filtrate by the treatment of 0.4 mol/L
aqueous solution of NaOH. It is interesting to note that here aqueous
solution of NaOH is being added to neutralize aqueous acetic acid

42
J. Lal et al. / Catalysis Communications 27 (2012) 38–43
Scheme 2. Mechanistic routes for the synthesis of curcumin 3,4-dihydropyrimidinones.
solution, as chitosan is soluble in aqueous acetic acid solution and
precipitated out on addition of NaOH solution. The pH at the end is
neutral. Recovered catalyst can be reused directly. The catalytic activ-
ity of the recovered catalyst was investigated (Fig. 3) for five consec-
utive times. The results show that there is no significant decrease in
reaction yield. The structural changes in chitosan were evaluated
using 1 NMR spectra of chitosan catalyst before applying in the reac-
tion (Fig. 4) and after recycling (Fig. 5) and observed that both the
spectra of chitosan (before applying and after recycling) were the
same which clearly indicates that, catalyst is stable during the
reaction.
excellent yield. The catalyst used in the procedure is recyclable,
non-toxic, and biodegradable.
Acknowledgments
The authors are indebted to M.P.C.S.T. Bhopal for financial support
(Grant no. 4468/CST/R&D/2010) and the director of SAIF, Punjab Uni-
versity, Chandigarh.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.06.017.
3.3. Mechanistic investigations
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reaction time, environment friendly, simple workup procedure with

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