Synthesis of biologically active chalcon analogues via claisen-schmidt condensation in solvent-free conditions: Supported mixed addenda heteropoly acid as a heterogeneous catalyst

Article abstract of DOI:10.4067/S0717-97072013000300029

Biologically active chalcones were synthesized via Claisen-Schmidt condensation of aldehydes with different ketones in solvent-free conditions using H5PMo10V2O40 supported on SiO2 as a reusable heterogeneous catalyst with excellent reusability.

Full text of DOI:10.4067/S0717-97072013000300029

J. Chil. Chem. Soc., 58, Nº 3 (2013)
SYNTHESIS OF BIOLOGICALLY ACTIVE CHALCON ANALOGUES VIA CLAISEN-SCHMIDT
CONDENSATION IN SOLVENT-FREE CONDITIONS: SUPPORTED MIXED ADDENDA HETEROPOLY ACID AS
A HETEROGENEOUS CATALYST
EZZAT RAFIEE* AND FARZANEH RAHIMI
Faculty of Chemistry, Razi University, Kermanshah, 67149, Iran
(Received: March 14, 2013 - Accepted: May 20, 2013)
ABSTRACT
Biologically active chalcones were synthesized via Claisen-Schmidt condensation of aldehydes with different ketones in solvent-free conditions using
H5PMo10V2O40 supported on SiO2 as a reusable heterogeneous catalyst with excellent reusability.
Keywords: Chalcone, Claisen-Schmidt condensation, mixed addenda, heteropoly acid, heterogeneous catalyst.
INTRODUCTION
NMR (200 MHz, CDCl3) δ 21.5, 28.3, 35.2, 122.0, 125.4, 126.2, 127.4, 128.3,
131.2, 132.7, 135.6, 142.8, 148.1, 190.2; IR (KBr) 1660 (C=O), 1620 (C=C)
cm-1; MS m/z 388.16; Anal Calcd. for C29H24O (388.18): C, 89.66; H, 6.23.
Found: C, 89.63; H, 6.25.
Chalcones belonging to flavonoid family have displayed a broad spectrum
of biological activities, among which antimalarial1, anticancer2, antimitotic3,
antibacterial4, antiADIS5, antihyperglycemic6 activities have been reported.
These compounds are of high interest due to their use as a key precursor in the
synthesis of many biological important heterocycles such as benzothiazepine7,
pyrazolines8 and flavones9. Thus, the organic/pharmaceutical chemists
worldwide have paid more attention to the synthesis of chalcones. Chalcones
could be obtained via Claisen-Schmidt condensation carried out in basic or
acidic media under homogenous conditions10. There are many drawbacks
under homogenous conditions including catalyst recovery and waste disposal
problems. Heterogeneous processes are industrially favor catalytic processes
in view of the ease of handling, simple work- up and regenerability. There
are different kind of catalysts which have been used for the Claisen-Schmidt
condensation, including Lewis acids11, Brönsted acid12, solid acid13, solid
bases14, and other catalysts with more or less success15,16. The increasing concern
about the tight legislation on the maintenance of greenness in synthetic strategy
led us to develop a method using green catalyst that is active in solvent-free
conditions as an alternative to volatile organic solvents. Here we have studied
the solvent-free Claisen- Schmidt condensation reaction using heteropoly acids
(HPAs) as solid acid catalysts that are metal- oxygen clusters and they have
attracted much attention as catalyst in organic reactions because of their high
RESULTS AND DISCUSSION
In the beginning of the study, cyclohexanone and benzaldehyde were used
as model reactants in order to find the optimum reaction conditions by Claisen-
Schmidt condensation using HPAs as catalysts (Scheme 1).
Scheme 1. Model reaction.
Without the addition of the catalyst, no product was formed even after
2 hrs. Various types of mixed addenda catalysts with different ratio of
molybdenum to vanadium were evaluated for the synthesis of chalcones.
H PMo10V2O40 (Mo V ) showed excellent reactivity among different kinds of
th5e catalysts (Table110 ).2
Brönsted acidity and redox properties17,18
.
EXPERIMENTAL
Table 1. Synthesis of chalcones using different HPA catalysts.
Entry
Catalysta
Time (min)
Yield (%)b
General
The reagents and solvents used in this work were obtained from Fluka,
Aldrich or Merck and were used without further purification. The commercial
Aerosil silica (SBET, 311 m2g−1; pore volume, 1.7 cm3g-1) from Degussa
was used. The catalyst sample was characterized with a scanning electron
microscope (SEM) (Philips XL 30 and S-4160) with gold coating.
1
2
3
4
5
6
-
120
15
25
40
10
50
0
Mo10V2
98
93
95
98
10c
Mo9V3
Mo8V4
Typical procedure for Claisen-Schmidt condensation
To a mixture of ketone (1 mmol) and aldehyde (2 mmol for Table 2; 1
mmol for Table 3), Mo V2/SiO2 (produced 40 wt.%: of Mo V2 to silica19, 32.5
wt.% from ICP result, 1t0ypically, the Mo content from ICP10was slightly lower
than expected from the preparation stoichiometry) (0.06 g, 0.085 mol% of
Mo10V2 to ketone as substrate) was added and crushed at 50 °C for appropriate
time. Completion of the reaction was monitored by TLC, using n- hexane/
ethylacetate (10:4) as eluent. After completion of the reaction, 2×10 mL of
ether was added to the mixture and filtered off. Catalyst was washed with
ether and dried for reusing. The solvent of the filtrate was evaporated then
followed by chromatography to obtained pure products. Spectroscopic data of
the products matched well with those in the literature20-23 and analytical data for
new compounds are presented below:
Mo10V2/SiO2
Mo10V2/SiO2
a)Isolated yield.
b) Reaction conditions: cyclohexanone (1 mmol), benzaldehyde (2 mmol),
catalyst (0.06 g), solvent-free, 50 ˚C.
c) Reaction proceed at room temperature.
HPAs with Keggin structures are flexible in their acid strength and
have low toxicity and fairly high thermal stability, so they are excellent and
versatile catalysts for a wide variety of organic reactions in both homogeneous
and heterogeneous media24,25. By immobilization of HPAs into convenient
carriers, the reaction easily carry out in a heterogeneous which has some
advantages like increase the accessibility to the acid sites and control solid acid
strength. Moreover, wastes are not produced, helping to incorporate in clean
technologies. Porous silica is one of the solids that has been mainly used for
supporting HPAs in various acid catalyzed reactions so here silica was used as
support for Mo10V2 and as shown in Table 1, the minimum of the reaction time
was need when this catalyst used in the model reaction that is due to increase
in the surface area of the catalyst. When the reaction was carried out in room
2,6-Bis-naphthalen-2-ylmethylene-cyclohexanone (2e, C28H22O) Yellow
solid; Mp: 281-282 °C, 1H NMR (200 MHz; CDCl3, TMS) δ 1.45 (m, 2H), 2.78
(t, 4H, J=5.6), 7.28-7.58 (m, 12H), 7.61 (s, 2H); 13C NMR (200 MHz, CDCl3)
δ 24.4, 28.1, 122.6, 125.5, 126.2, 127.4, 129.2, 133.0, 132.3, 133.8, 143.4,
149.3, 190.2; IR (KBr, cm-1) 1660 (C=O), 1622 (C=C) cm-1; MS m/z 374.16;
Anal Calcd. for C28H22O (374.17): C, 89.81; H, 5.92. Found: C, 89.83; H, 5.90.
4-Methyl-2,6-bis-naphthalen-2-ylmethylene-cyclohexanone (2f, C29H24O)
Yellow solid; Mp: 288-290 °C, 1H NMR (200 MHz; CDCl3, TMS): δ 7.69 (s,
2H), 1.51 (d, 3H, J=6.2), 1.63 (m, 1H), 2.81 (m, 4H), 7.29-7.56 (m, 12H); 13
C
e-mail: ezzat_rafiee@yahoo.com
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J. Chil. Chem. Soc., 58, Nº 3 (2013)
temperature, there is no significant progress in the reaction so reaction was
carried out in 50 ˚C.
The morphological feature of the Mo10V /SiO catalyst was investigated
by SEM techniques. Fig. 1(a) shows the SEM2micr2ograph of the catalyst. The
particles are regular in shape and dispersed uniformly. Wavelength dispersive
X-ray (WDX) image studied that is the map of individual elements of Si, Mo
and V elements in cross-section were shown in Fig. 1(b). It showed an excellent
uniform distribution of Mo10V2 on SiO2 surface.
Scheme 2. Synthesis of cahcones with cyclic ketones.
To investigate the generality of the method a variety of aldehydes
were used in the optimized reaction conditions with cyclohexanone and
4-methylcyclohexane as cyclic ketones (Scheme 2). In most cases the reaction
proceeded smoothly to produce the corresponding chalcones. The reactions
were found to be clean and the products were obtained in excellent yields
without the formation of any side products (Table 2).
Table 2. Synthesis of different chalcones from cyclic ketones using
Mo10V2/SiO2 as catalyst.
mp (°C)
Time Yield
Entry Aldehyde Product
(min) (%)a
Observed
116-117
Reported
O
1
2
2a
2b
10
20
98
96
115-11725
H
O
168-170
144-146
170-17125
147-14825
H
O
3
4
H
2c
20
30
97
95
Cl
Fig. 1. SEM images of (a) Mo10V /SiO2 and (b) elemental maps of Si, Mo
and V atoms of Mo10V2/SiO2 catalyst. 2
O
2d
288-290
289-29125
H
To optimize the catalyst loading model reaction was performed with
different amounts of the catalyst and the best result was obtained with 0.06 g of
Mo10V2/SiO2 as shown in Fig. 2.
HO
O
O
5
6
2e
2f
25
40
94
93
281-282
288-290
-
-
H
H
a) Isolated yield.
Encourage by these results, we decided to use aromatic ketones (Scheme
3) and as we expected the products were obtained with high yields and without
any byproducts (Table 3).
1
In the cases of 3a-3h products, H NMR spectral data clearly indicated
that the compounds were geometrically pure and were configured trans (JHα_Hβ
= 15–16 Hz). In other reactions (2a-2f products), we obtained only the E, E
isomer. In the spectra of compounds, the signals for the protons of the CH=
group appear at δ 7.41-7.81. It is known26-28 that the Z isomers are characterized
by the chemical shifts at δ ~6.8, whereas the signals for the E isomers should
appear at higher field than 7.2 ppm.
Fig. 2. Effect of the amount of the catalyst in the model reaction after 10
min.
Reaction of 1-methyl-4-pipridone as a heteroaromatic ketone with
4-cholorobenzaldehyde show 87% of 3,5-bis-(4-chloro-benzylidene)-1-
methyl-piperidin-4-one after 1 h29.
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J. Chil. Chem. Soc., 58, Nº 3 (2013)
Scheme 3.Claisen- Schmidt condensation reaction with aromatic ketones.
Table 3. Synthesis of different chalcones from aromatic ketones using Mo10V2/SiO2 as catalyst.
mp (°C)
Entry
R1
R2
Product
Time (min)
Yield (%)a
Observed
Reported
1
2
3
4
5
6
7
8
–
Cl
–
–
3a
3b
3c
3d
3e
3f
20
24
45
20
45
25
40
30
96
98
97
95
90
95
91
92
54-56
111-112
97-98
54-5721
111-11321
97-9822
CH3
OH
–
–
–
178-180
98-100
172-174
158-160
193-194
181-18323
100-10123
173-17423
159-16026
191-19221
Cl
OH
_
–
NO2
OMe
3g
3h
NO2
a)Isolated yield.
The catalyst shows reusability in this reaction and the catalytic activity of
the catalyst has not significant decrease even after four runs and it shows that
Mo10V2/SiO2 is a good catalyst according the economics of reaction and green
chemistry purposes Fig. 3.
catalyst was successfully used in the synthesis of chalcones via Claisen-
Schmidt condensation of aldehydes with different ketones in solvent-free
conditions. The reactions were found to be clean and the products were obtained
in excellent yields from aromatic and cyclic ketones without the formation of
any side products. Excellent yields, selectivities, and environmentally friendly
procedure, with low cost, easy preparation with high reusability and handling
of catalyst are some of salient advantages of this method.
ACKNOWLEDGEMENTS
We thank the Razi University Research Council for support of this work.
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