Process for synthesis of Chalcones and Uses thereof
Field of the Invention:
The present invention relates to provide an extremely simple, rapid and high yielding
practical synthetic approach for a variety of chalcones using of p-toluenesulfonic acid 01-
TSA) as an efficient catalyst for the synthesis of chalcones under solvent-free conditions that
ruled out all the limitations of either acid or base catalysed reactions as well as microwave
conditions.
1 Background of the invention:
The most widely used method for the synthesis of chalcones is the base catalysed Claisen-
Schmidt reaction between aryl aldehydes and substituted acetophenones (Scheme 1).
Chalcone
Scheme 1: Claisen-Schmidt condensation
The earlier used methods for the synthesis of chalcones comprises expensive catalysts and
involve stringent and/or dry conditions, use of organic solvents, extended reaction times,
formation of side products, complex work-up procedures, poor yields and the use of
stoichiometric andlor relatively expensive reagents. Also most of these methods when used
for the synthesis of 2-hydroxy chalcones generally are accompanied by the formation of
flavanones and aurones via cyclization. Some acid catalysed reactions have also been
reported by using dry HCl gas, BF3 and AlC13 as reagents which make the process further
difficult to handle. Thus, development of more efficient methods is required which uses
proper catalysts to make the available procedures more convenient and simple that can be
used for compounds containing base sensitive functionalities.
1306/MUM/2009 is related to the synthesis and characterization of novel coumarin chalcones
chromophores prepared from condensation of 8-acetyl-l,4,-dialkyl-l,2,3,4-tetrahydro-7Hpyrano
[2,3-g] quinoxalin-7-one with various substituted benzaldehyde derivatives but the
application has been withdrawn.
2462/DEL/2007 is related to novel antimalarial acylhydrazones of chalcones and process for
the preparation thereof. The invention involves mixing a ketone and an aldehyde in the molar
ratio of 1 : 1 to 1 :5 in 1-3 N alcoholic NaOH or KOH at room temperature for 40-240 minutes,
ii.washing the reaction mixture with acidic water to obtain the product chalcones. This
invention is evidently different from the present application which claims the use of ptoluenesulfonic
acid @-TSA) as an efficient catalyst instead of using alcoholic NaOH or
KOH in the above mentioned prior art.
2724/DEL/2005 provides process using aqueous NaOH in methanol at room temperature to
obtain chalcones which again is different from the present application.
6511/DELNP/2010 provides method for preparing 3-Trifluoromethyl chalcones using
alkaline earth metal hydroxides and compounds capable of forming said alkaline earth metal
hydroxides on contact with water and the said method is based on forming a low boiling
azeotrope with water or by using a Grignard reagent.
(CN102093274) relates to Chalcone-containing acylthiourea compounds and preparation
method and use thereof. The compounds are prepared by reacting acyl chloride with
ammonium thiocyanate in the presence of a phase transfer catalyst in a protonic solvent to
obtain acylisosulfocyante, reacting acylisosulfocyante with aminoacetophenone to obtain Nbenzoyl-
N'-acetylphenylthiourea, and performing condensation of N-benzoyl-N1-
acetylphenylthiourea and aromatic aldehydes under an alkaline condition to obtain target
compounds. This is different from the present application.
(W02011064726) Method for the synthesis of aspalathin and analogues thereof provides
for the step of coupling a sugar to a dihydrochalcone, chalcone or flavanone, or coupling the
sugar to an intermediate for producing a dihydrochalcone, chalcone or flavanone followed by
coupling of the sugar-intennediate adduct to a further intermediate for producing a
dihydrochalcone, chalcone or flavanone, and transforming the product thereof into a
compound of formula 1 or an analogue or derivative thereof.
(CN102850202) Method for preparing chalcone by fluorous biphasic catalysis with
fluoride-free solvent discloses a method for preparing chalcone by fluorous biphasic
2
e
catalysis with fluoride-free solvent. The method comprises the following steps: dissolving
DMAP (dimethylamino pyridine) and fluorine-containing alkyl iodide into dichloromethane,
stirring at room temperature for reaction to generate white solid, drying at high temperature
in vacuum to obtain fluorine-containing DMAP; adding fluorine-containing DMAP into a
reactor containing normal octane, and then adding acetophenone and benzaldehyde to
perform condensation reaction, and raising the temperature for heating; cooling and filtering
the mixed solution obtained from the condensation reaction to recycle the catalyst;
evaporating out the solvent to recycle; recrystallizing the product to obtain pure chalcone. In
this invention, the catalyst is fluorous based whereas the present application deals with p-
TSA as the catalyst.
None of the cited references above disclose or teach what the present invention discloses or
teaches. The present invention distinguishable over these cited prior art references.
The present invention is related to the novel application of p-toluenesulfonic acid @-TSA) as
an efficient catalyst for the synthesis of chalcones under solvent-free conditions. The catalytic
reaction using (p-TSA) overcomes the limitations of either acid or base catalysed reactions as
well as microwave conditions. The present invention focuses on the catalytic evaluation of ptoluenesulfonic
acid by taking benzaldehyde and acetophenones as model substrates.
The present protocol has also been found to be highly useful for the condensation between 2-
hydroxy acetophenones and aryl aldehydes which selectively led to the formation of 2-
hydroxy chalcones without any cyclized side products. Further, the reaction time has also
been reduced from hours to few minutes and the yields achieved are much better than those
used in the prior arts.
It is for the first time when only p-toluenesulfonic acid has been used for Claisen Schmidt
condensation reaction without the use of any expensive reagents or apparatus like microwave
etc. to synthesize a wide variety of chalcones derivatives vehemently under solvent-free mild
conditions.
Another important advantage is isolation ofp-TSA catalyst which can be used again.
Summary of the Invention
The present invention results in a very simple, solvent free and highly expeditious method to
prepare a wide variety of chalcone derivatives using p-toluene sulfonic acid @-TSA), thereby
disclosing the use of p-TSA as a green organocatalyst which accelerates the Claisen Schmidt
condensation reaction dramatically under very mild conditions affording high yields.
The invention provides an acid catalysed protocol which is not only simple but also
eliminates the formation of cannizaro's products. The present approach is an elegant and
highly useful for the condensation reaction specifically between 2-hydroxy acetophenones
and aryl aldehydes which selectively leads to the formation of 2-hydroxy chalcones without
any cyclized side products.
Detailed description of the invention
Chalcones represent an important class of natural compounds with a variety of biological
activities and are represented by the following structural formula (Fig. 1).
Fig. 1
In recent years, chemistry of both natural and synthetic chalcones have has attracted more
attention because these compounds have been found to exhibit various biological activities
like anticancer, antimalarial, antimicrobial, anti-inflammatory activities, anti-HIV, antiviral,
anti-hyperglycemic and tyrosinekinase inhibitory activities.
Licochalcone A (Fig.2) isolated from the roots of Glycyrrhiza injZata (licorice) possesses in
vitro as well as in vivo antimalarial and antileishmanial activity. 3-Methoxy-4-
hydroxyloncocarpin (Fig.3) obtained from the roots of Lonchocarpusutilis inhibits NADHubiquinone
oxidoreductase activity (Narender, T., Reddy, K.P., Tetrahedron Letters, 2007,
48,3 177-3 180).
Recently, it has been reported that coumarin chalcones (Fig.4) act as potent anticancer agents
used in treatment and prevention of cervical, oral squarnous, lung, prostate carcinoma and
brain tumors. Moreover, these chalcone derivatives are selective for the cancerous cell and
did not harm normal cells (Sashidhara, K., Sashidhara, V., Kumar, A., Kumar, M., Sarkar, J.,
Sinha, S., Sinha, K., WO 201 2/01 7454A1 (201 2). Poter et a1 have reported that substituted 1 -
(4-methoxypheny1)-3-(3,5-dimethoxypheny1)prop-1 - en-3-ones (Fig.5) exhibited antiproliferative
and anti-inflammatory activities (Poter, G.A., Butler, P.C., Wanogho, E.,
US6787672 B2 (2004).
x OMe
Apart from medicinal uses, they are also used in food additives and ingredients in cosmetic
formulations (Bertrand, K., Roudot, A., Rool, P., WO 201 11144579Al (201 1)). Some
derivatives are used as sweeteners, drugs, and sunscreen agents. Chalcones are the main
precursors for the biosynthesis of flavonoids which are frequent components of the human
diet. They are abundant in commonly consumed fruits and vegetables such as apples, pears,
strawberry, bearberry and tomatoes respectively. In addition, they are also present in wheat
and wheat products. The most common chalcones occur in fruits and vegetables include
phloretin, phloridzin, chalconaringenin and arbutin. These derivatives also act as useful
precursors for the synthesis of many medicinally important heterocyclic moieties like
5
pyrazolines, benzodiazepines, 1,4-diketones and flavones (Siddiqui, Z.N., Musthafa, T.N.M.,
Tetrahedron Letters, 20 1 1, 52,4008-40 13).
Need of Invention:
Of the numerous synthetic approaches available for chalcones, the most widely used is the
base catalysed Claisen-Schmidt reaction between aryl aldehydes and substituted
acetophenones (Scheme 1).
Chalcone
Scheme 1 : Claisen-Schmidt condensation
Besides drawbacks of using expensive catalysts, some of the methods involve stringent
and/or dry conditions, use of organic solvents, extended reaction times, formation of side
products, complex work-up procedures, poor yields and the use of stoichiometric andlor
relatively expensive reagents. Also most of these methods when used for the synthesis of 2-
hydroxy chalcones generally are accompanied by the formation of flavanones and aurones via
cyclization. Some acid catalysed reactions have also been reported by using dry HC1 gas, BF3
and AlC13 as reagents which make the process further difficult to handle. Thus, development
of more efficient methods and exploring proper catalysts are still in demand to make the
available procedures more convenient and simple that can be used for compounds containing
base sensitive functionalities.
Detailed Description of Work Done:
Owing to widespread availability and therapeutic potential of chalcones and in continuation
of our work related to explore efficient and novel greener synthetic methodologies for
important key intermediates and biologically active heterocycles it was envisaged to perform
and study the Claisen Schimdt reaction usingp-TSA under solid phase conditions.
Herein, we report the novel application of p-toluenesulfonic acid (p-TSA) as an efficient
catalyst for the synthesis of chalcones under solvent-free conditions that ruled out all the
above mentioned limitations of either acid or base catalysed reactions as well as microwave
6
a conditions. Preliminary efforts were mainly focused for the catalytic evaluation of ptoluenesulfonic
acid by taking benzaldehyde and acetophenones as model substrates. To
observe the effect of temperature, as well as the amount of p-toluenesulfonic acid required,
different reactions were carried out using 1 equiv. of benzaldehyde (la) and 1 equiv of.
acetophenone (2a) in the presence of p-toluenesulfonic acid under solvent-free conditions at
different temperatures (Scheme-2, Table 1).
+ H3C p-TSA
t
0 0 solid phase
Scheme 2: Claisen-Schmidt condensation using p-TSA
Initially, a reaction between 1 a and 2a was performed at room temperature for 60 minutes and
resulted the recovery of starting materials without the traces of the product 3a (entry 1). After
the analysis of 'H NMR spectrum of a crude mixture it has been confirmed that reaction
between 1 a and 2a could not succeed.
Table 1. Reaction of la and 2a under different temperaturesa
Entry p-TSA (equiv) Temp('C) Time (min.) 3a (%)
5 2 50 2 9 8
a Condition: 1 equiv of la was treated with lequiv of 2a under a solvent-free condition.
b~eactiown as monitored on the basis of TLC.
To explore the catalytic potential of p-toluenesulfonic acid (p-TSA), a similar reaction was
carried out at room temperature in the presence of 1 equiv of p-TSA for the preparation of 3a,
in which 35% of 3a has been formed within 15 minutes (entry 2), however with 2.0
7
e equivalents p-TSA, 90 % conversion of reactants into product has been achieved at the same
temperature with in 15 minutes.
But the reaction surprisingly resulted into the exclusive formation of the product 3a in 97%
yield (entry 4) at 50-60 'C in presence of 1.0 equivalent p-TSA within 2-4 minutes. In order
to optimize the amount of p-TSA required for the above transformation, different
experiments were carried out by varying the amount ofp-TSA at different temperatures. It
has been found that either using 1 or 2 equivalents of p-TSA at 50-60 "C always resulted in
the exclusive formation of 3a in 90-98 % yields. These results clearly indicated that the use of
1 equivalent catalyst is sufficient to synthesize the chalcone derivatives in excellent yields.
After choosing the best condition using bezaldehyde (la) and acetophenones (2a), the
generality of the p-toluenesulfonic acid catalyzed reaction was examined by selecting a
number of aryl aldehydes as well as various substituted acetophenones (Table 2). As
expected, excellent yields were obtained for compounds3 generated under solvent-free
condition at 50-60 'C within 2-5 minutes. All the synthesized compounds were characterized
on the basis of IR, 'H, I3c NMR and Mass spectral data.
The present protocol has also been found to be highly useful for the condensation between 2-
hydroxy acetophenones and aryl aldehydes which selectively led to the formation of 2-
hydroxy chalcones without any cyclized side products. The reaction time was reduced from
hours to few minutes and the yields were achieved much better (Table 2). To the best of our
knowledge it is for the first time when only p-toluenesulfonic acid has been used for Claisen
Schmidt condensation reaction without the use of any expensive reagents or apparatus like
microwave etc. to synthesize a wide variety of chalcone derivatives (3) vehemently under
solvent-free mild conditions.
Another important advantage is isolation of p-TSA catalyst which can further be used.
Further research work on such types of condensation reactions and others (e.g. reaction of
pyrazole aldehydes with acetophenones or aliphatic acyclic or cyclic ketones and reaction of
DHA with acetophenones) is still continued in our lab with an aim to explore the further
synthetic utility ofp-TSA in the field of organic synthesis.
Table 2.Physical data of chalcones 3 obtained by solvent-free conditions in presence of p-
TSA
Entry Products R= R -CsH5-, R' = R"'-c~H~-,o~Ti me Isolated yield Mp. ("C) Rf value
(3) thienyl (minutes) (%)
Or thienyl
Mechanism of Claisen-Schmidt Reaction Using p-TSA
A plausible mechanism for the Claisen-Schmidt condensation between acetophenone and
benzaldehyde in presence of p-TSA may involve the steps shown in Scheme-3.
/ 2 0 3 t Thein-2-yl 4-CH3 4 95.01% 140
I
0.4
I 21 3~ - H 2-OH 4 90.23% 89-90 0.4
2 2 3~ 4-CH3 2-OH 2 91.21% 105-106 0.5
23 3~ 4-OCH3 2-OH 3 85.21% 90-91 0.5
-TG] +'d- H : 6jH +ij. H &:: keto-enol
H - step-I & H tautomerism
Ketone protonated ketone enol protonated
- w w
I aldehyde
step-2
0 H
& H+ chalcone -H20 & H H /
step3
Scheme 3: Plausible mechanism
Outcome of the Invention:
In conclusion, a very simple, solvent free and highly expeditious method to prepare a wide
variety of chalcone derivatives (3) using p-toluene sulfonic acid (ID-TSA) has been developed.
For first time it disclosed the use of p-TSA as a green organocatalyst which accelerates the
Claisen Schmidt condensation reaction dramatically under very mild conditions. The
syntheses of chalcone derivatives which have already been reported earlier in solvent medium
10
and/or in presence of bases result poor yields besides the formation of side products. Herein,
we provide an acid catalysed protocol which is not only simple but also eliminates the
formation of cannizaro's products. The present approach is an elegant and highly useful for
the condensation reaction specifically between 2-hydroxy acetophenones and aryl aldehydes
which are selectively led to the formation of 2-hydroxy chalcones without any cyclized side
products. Mild reaction conditions, clean reaction media, very simple workup, exclusive
formation of products without side products, easy purification and recycling of the catalyst
are advantages of the present methodology.

We claim: '
1. A process for synthesis of chalcones comprising the steps of reacting aryl aldehydes
to substituted acetophenones in presence of catalyst p-TSA @-Toluene sulfonic acid)
under solvent free conditions.
2. The process as claimed in claim 1, wherein the catalyst selectively leads to the
formation of 2-hydroxy chalcones on condensation between 2-hydroxy acetophenones
and aryl aldehydes; the catalyst can be used to achieve yield upto 100%.
3. The process as claimed in claim 1, wherein the said process provides an acidcatalysed
protocol which eliminates the formation of side products i.e. Cannizaro's
products.
4. The process as claimed in claim 3, wherein the yield of 97% can be achieved in less
than 4 minutes.
5. A process as recited in claim 3, wherein the temperature required is up to 50°C-60°C.
6. A process as recited in claim 3, wherein time taken for the reaction is up to15
minutes.
7. A process as recited in claim 3, wherein the yield achieved is 90% within 15 minutes.
8. A process as recited in claim 4, wherein the yield achieved is 97% within 4 minutes.
Dated this January 17,2014
INP A-389
Authorized Agent for the Applicant