Synthesis of flavanones, azaflavanones, and thioflavanones catalyzed by PMA-SiO2 as a mild, efficient, and reusable catalyst

Article abstract of DOI:10.1007/s00706-011-0663-7

Cyclization of a variety of chalcones to flavanones catalyzed by 1 mol% phosphomolybdic acid (PMA) supported on silica as a mild, efficient, and reusable catalyst was carried out in high yields. PMA-SiO₂ is an efficient, inexpensive, and green catalyst which gave high conversion yields and could be recycled up to three times without significant loss in activity. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0663-7

Monatsh Chem (2012) 143:797–800
DOI 10.1007/s00706-011-0663-7
ORIGINAL PAPER
Synthesis of flavanones, azaflavanones, and thioflavanones
catalyzed by PMA-SiO2 as a mild, efficient, and reusable catalyst
•
Raghavendra Sakirolla Marzieh Yaeghoobi
•
Noorsaadah Abd. Rahman
Received: 28 February 2011 / Accepted: 25 September 2011 / Published online: 12 November 2011
Ó Springer-Verlag 2011
Abstract Cyclization of a variety of chalcones to flava-
nones catalyzed by 1 mol% phosphomolybdic acid (PMA)
supported on silica as a mild, efficient, and reusable cata-
lyst was carried out in high yields. PMA-SiO2 is an
efficient, inexpensive, and green catalyst which gave high
conversion yields and could be recycled up to three times
without significant loss in activity.
can be performed using orthophosphoric acid, acetic acid,
and silica gel [8], while base catalysis has been carried out
with strong alkali [9] or L-proline [10]. Other cyclization
methods involve different reaction conditions such as light
[11], heat [12], electrolysis [13], and Ni/Zn/K halide
catalysis [14]. However, many of these methods suffer
from disadvantages such as low yield, long reaction time,
strong acidic medium leading to environmental pollution,
high catalyst cost, or lack of catalyst recovery and reus-
ability. Hence, there is still a need to develop mild, high-
yielding protocols for cyclization of substituted chalcones
to flavanones via an environmentally friendly method.
Phosphomolybdic acid supported on silica (PMA-SiO2)
belongs to the class of heteropolyacids (HPA) and has
gained importance [15] as a catalyst since it is inexpensive,
environmentally friendly, and stable at high temperature.
Some examples where HPAs have been used as catalysts
include Fries rearrangement of phenyl acetate [16], Fri-
edel–Crafts acylation of phenols [17], oxidation of alcohols
[18], aziridination of olefins with chloramine-T [19], reg-
ioselective opening of aziridines with nucleophiles [20],
chemoselective hydrolysis of acetonides [21], Ferrier
rearrangement [22], and Nazarov rearrangement [23].
Keywords Chalcones Á Heteropolyacid Á Acidity Á
Cyclization Á Flavanone
Introduction
Flavonoids are found abundantly in plants of the families
Leguminosae, Compositae, and Moraceae. They have been
reported to possess a broad spectrum of biological activity
[1] such as anti-inflammatory, antitumor [2], antioxidant,
and estrogen receptor modulator activities [3]. In addition,
they have been observed to inhibit the activity of
cyclooxygenase/lipoxygenase [4]. Their azaflavanone deri-
vatives have been reported to have potential as candidate
nonsteroidal anti-inflammatory drugs (NSAIDs) [5], while
the thioflavanone derivatives have been shown to serve as
precursors for biologically active compounds such as
benzothiazepine and thiochroman-4-one [6]. Synthesis
of flavanones often involves intramolecular conjugate
addition of 2-hydroxychalcones, 2-aminochalcones, and
2-mercaptochalcones to the corresponding cyclic system
through acid or base catalysis. Acid-catalyzed reactions [7]
Results and discussion
Cyclization reactions of chalcones to flavanones using
PMA-SiO2 as a catalyst were carried out. PMA-SiO2
(1 mol%) catalyzes 2-hydroxychalcone to the correspond-
ing flavanone by intramolecular cyclization. Following
completion of the reaction, the catalyst was recovered with
a simple workup and filtration for reuse. As shown in
Table 1, the recovered catalyst did not show any appre-
ciable loss in activity, with more than 87% yield of the
R. Sakirolla Á M. Yaeghoobi Á N. Abd. Rahman (&)
Department of Chemistry, University of Malaya,
50603 Kuala Lumpur, Malaysia
e-mail: noorsaadah@um.edu.my
123

798
R. Sakirolla et al.
polarity. Highly polar solvents may enhance the activity of
the catalyst due to hydrogen bonding. Thus, the polarity of
the solvent plays a key role.
Table 1 Catalyst recycling in cyclization of 2-hydroxychalcone
catalyzed by PMA-SiO2
O
O
Cl
Cl
1 mol% PMA-SiO2
All the reactions occurred smoothly, as presented in
Tables 2 and 3. o-Hydroxychalcones reacted faster than
2-mercaptochalcones and 2-aminochalcones to give the
corresponding flavanones in excellent yields. The reaction
time for mercaptochalcones was not significantly longer
than for hydroxylchalcones, but lower yields of product
were obtained with the mercaptochalcones even after stir-
ring for a longer time. In addition, thioflavanones have not
been previously prepared from mercaptochalcones,
although thiols are more nucleophilic than alcohols and
amines due to the soft nature of thiols. The low reactivity
of mercaptochalcones may be attributed to the fact that
thiols tend to oxidize easily to form disulfides [24].
In a typical experiment, a solution of substituted chal-
cones in ethanol was stirred with 1 mol% PMA-SiO2 under
reflux. The reaction was completed in about 8.5 h. The
catalyst was removed by filtration and could be reused up
to three times without appreciable loss in catalytic activity
and yield, as presented in Table 1. The optimal quantity of
Ethanol, reflux, 8.5 h
H3C
OH
H3C
O
Condition
Yield/%
1 mol% PMA-SiO2, reflux, 8.5 h
1st recycle, reflux, 8.5 h
93
91
89
87
2nd recycle, reflux, 8.5 h
3rd recycle, reflux, 8.5 h
flavanone obtained even when the catalyst was reused for
the third time.
In addition, use of different solvents for the cyclization
reaction of hydroxychalcone indicated that PMA-SiO2
performs best in ethanol and only moderately in acetoni-
trile. The difference in the reactivity of catalyst in
acetonitrile and ethanol could be explained based on the
Table 2 1 mol% PMA-SiO2-catalyzed cyclization of chalcones
O
O
R1
1 mol% PMA-SiO2
R1
R2
R2
Ethanol, reflux
X
XH
R3
R3
Entry
X
R1
H
R2
R3
Time/h
Yield/%a
M.p./°C
(observed)
M.p./°C
(reported)
Ref.
1
O
O
O
O
O
O
O
NH
NH
S
NO2
OCH3
Cl
H
8
98
93
96
94
94
97
80
55
52
86
88
90
84
156
150
179
148
185
91
161–163
154
[27]
[28]
[28]
[28]
[29]
[28]
[30]
[30]
[30]
[31]
[31]
[31]
[31]
2
OCH3
H
H
9
3
H
9
185–187
155–158
190–192
97
4
H
OCH3
OH
H
H
9
5
H
H
9
6
H
H
8.5
9
7
H
CH3
OCH3
H
H
89
82–83
8
H
H
17
18
9.5
9.5
9.5
9.5
140
140
50
147
9
H
H
149–150
56–57
10
11
12
13
H
H
H
S
H
Cl
H
126
116
90
126–127
116–117
93–94
S
H
H
NO2
H
S
H
OCH3
1
All products characterized by H nuclear magnetic resonance (NMR) and mass spectral data
a
Yield of isolated product
123

Synthesis of flavanones, azaflavanones, and thioflavanones
799
Table 3 1 mol% PMA-SiO2-catalyzed cyclization of chalcones in ethanol under reflux
O
O
O
R1
R2
R1
1 mol% PMA-SiO2
Ethanol, reflux
R2
OH
Entry
R1
Cl
R2
Time/h
Yield/%a
M.p./°C (observed)
M.p./°C (reported)
Ref.
1
2
CH3
H
8.5
93
85
140
138
142
[10]
[32]
OCH3
10.5
141–142
1
All products characterized by H NMR and mass spectral data
a
Yield of isolated product
Acknowledgments R.S. and M.Y. thank the University of Malaya
for their fellowships, and the authors acknowledge the Malaysian
Ministry of Science, Technology, and Innovation (MOSTI) through
IPharm for grant no. 53-02-03-1049.
catalyst was found to be 1 mol%. Excess amount of cata-
lyst did not increase the yields (Tables 2, 3). In all cases,
the flavanone (about 93%) was obtained exclusively as
confirmed by spectroscopic data [10].
In summary, PMA-SiO2 is an efficient and reusable
catalyst for cyclization of various chalcones to flavanones.
The simple protocol, low cost of the catalyst, reusability,
and environmental considerations make this procedure
useful and attractive.
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A mixture of PMA-SiO2 (1 mol%) and chalcone (1 mmol)
in 5 cm3 EtOH under N2 atmosphere was stirred under
reflux for the appropriate time (Tables 2, 3). The reaction
was monitored by TLC, and after completion the solvent
was removed under reduced pressure and the residue was
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