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P. Zubaidha et al / Chemistry Journal (2012), Vol. 02, Issue 03, pp.

106-110

ISSN 2049-954X

Research Paper

An Improved and Eco-Friendly Method for the Synthesis


of Flavanone by the Cyclization of 2-Hydroxy Chalcone
using Methane Sulphonic Acid as Catalyst
Pramod Kulkarni1, Pradip Wagh1 and Pudukulathan Zubaidha1*
1

School of Chemical Sciences, S.R.T.M. University, Nanded 431606 (MS) India


Tel. No. +912462229518 Fax: +912462229245
*1E-Mail: pzubaidha20001@yahoo.co.in

Abstract
Flavanones are important biosynthetic precursors for the synthesis of flavones, isoflavones, flavonols and dihydroflavonols.
The flavanone skeleton is present in a wide range of synthetic and naturally occurring products exhibiting various
interesting pharmacological activities. The present paper describes the use of methane sulphonic acid as an efficient
organocatalyst for the synthesis of substituted flavanones from 2-Hydroxy Chalcones in good yields and in short reaction
time. The catalytic efficiency of methane sulphonic acid in cyclization of chalcones to flavanones has been demonstrated
with a variety of substrates bearing electrondeficient to electron rich groups on chalcones and the yields obtained are
higher than the reported methods with triflluoroacetic acid / mineral acids. Methane sulphonic acid is an inexpensive, safe,
eco-friendly acid catalyst with low LD50. The present protocol could find wide spread application in the synthesis of
flavanones bearing free hydroxyl groups on the aromatic moiety. At the same time the methodology would be useful for the
synthesis of naturally occurring bioactive flavanones.
Keywords: Methane Sulphonic Acid, 2-Hydroxy Chalcone, Flavanone, Cyclization, Acetic acid

1. Introduction
Flavanones (2,3-dihydro-2-phenyl-4H-1-benzo-pyran-4one derivatives) are the main biosynthetic precursors for
major flavonoids such as flavones or isoflavones and for
two important flavonoid intermediates: the flavan-4-ols
(biosynthetic precursors for the formation of 3deoxyanthocyanins)
and
the
dihydroflavonols
(biosynthetic intermediates in the formation of catechins,
flavonols, anthocyanins and proanthocyanidins) (Heller &
Forkmann, 1988; Haslam, 1993 and Mann, 1994). The
flavanone skeleton is present in a wide range of synthetic
or naturally occurring products exhibiting various
interesting pharmacological activities (Bertram, 1989;
Pathak et al, 1991; Spilkova & Hubik, 1992 and Manach et
al, 1996). Flavanones widely distributed in nature,
continue to attract attention due to their ample range of
biological activities (like hypotensive, antifungal,

antibacterial, antitumoral) (Middleton & Kandaswami,


1994; Harborne & Williams, 2001; Nijveldt et al, 2001;
Wang et al, 2001 and Heim et al, 2002).
The cyclization of chalcones to Flavanones has been
reported using acids (Reichel & Proksch, 1973 and
Chaturvedi et al, 1992 ), bases (Keane et al, 1970; NabaeiBidhendi & Bannerjee, 1990 and Wurm & Schnetzer,
1992), silica gel (Bagade et al, 1991), heat (Harris &
Carney, 1967 and Hoshino & Takeno, 1986), light
(Stermitz et al 1975; Matsushima & Kageyama, 1985;
Pandey et al, 1987 and Maki et al, 1988), electrolysis
(Sanicanin & Tabakovic, 1986), Cobalt (II) Schiff-base
complexes (Maruyama et al, 1989), zeolites (Climent et al,
1995),L-Proline (Chandrasekhar et al, 2005) and
microwave conditions (Sagreraa & Seoane, 2005) but the

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P. Zubaidha et al / Chemistry Journal (2012), Vol. 02, Issue 03, pp. 106-110

obtained yields are often moderate and sometimes poor.


The acid catalyzed cyclization can be carried out by
refluxing the chalcone in acetic acid or also in ethanol or
other suitable solvent in the presence of an acid catalyst
such as H3PO4 (Sagrera et al, 1998). Flavanones can also
be obtained from precursors other than chalcones, namely
by (i) reacting 3-chloro-2,3-dihydro-3-nitro-2-phenyl-4H1-benzopyran-4-ones with tributyl tin hydride and 2,2azobisisobutyronitrile (Dauzonne & Monneret, 1997) (ii)
treating 3-bromo-1-phenyl prop-2-ynil aryl ethers with
mercury
(II)
trifluroroacetate
(Subramanian
&
Balasubramanian, 1990) (iii) oxidizing flavan-4-ols
(Bhatia et al, 1968) (iv) treating 1-(2-hydroxyphenyl)-3phenyl-propane-1,3-diones with benzaldehydes (Joglekar
& Samant, 1988).
Methane sulphonic acid is a clear colourless liquid
available as a 70% solution in water and anhydrous form.
The structure of methane sulphonic acid lends itself to
many catalytic reactions, due to its high acid strength (PKa
= -1.9) and low molecular weight (96.0 g/mol). Further it
is easy to handle methane sulphonic acid as liquid and can
be recyclized. The other attributes includes low LD50 and it
is biodegradable forming sulphate and CO2. Methane
sulphonic acid is considered to be natural product and is
part of the natural sulfur cycle (Commarieua et al, 2002).
Also as a Bronsted acid it has been widely used to catalyze
wide variety of reaction and as solvent for condensation
and rearrangement reaction (Sharghi, 1998; Kaboudin,
1999 and Leleti et al, 2007).
Therefore, there is scope to develop a new method for the
synthesis of flavanone by using an inexpensive, safe,
simple and eco-friendly catalyst i.e. methane sulphonic
acid. To, the best of our knowledge, there is no report on
the use of methane sulphonic acid as catalyst for the
cyclization of 2-hydroxy chalcone into flavanone.

The hydroxy flavanone was purified


chromatography using MeOH: CHCl3.

2.1. General Procedure for Cyclization of 2-Hydroxychalcone to Flavanone


A mixture of 2-hydroxy chalcones (1.0 mM), catalytic
amount of methane sulphonic acid (10 mol %) in acetic
acid was subjected to reflux for 2 hours. Workup with
water afforded flavanone as solid which was filtered off
and purified by column chromatography using ethyl
acetate: petroleum ether (9:1) as eluent to get pure product.

column

When refluxed in acetic acid in the presence of methane


sulphonic acid, chalcones (I) were transformed into
equilibrium mixture containing (I a) and isomeric
flavanone (II a), in 2 hours, the latter being the
predominant component ( Scheme 1). To study the
effect of solvent on equilibrium ratio, the reaction was
performed in various solvents such as acetic acid, ethanol,
DMF and DMSO. The reaction proceeds well in acetic
acid compared to other solvents. The results are shown in
Table 1.
R4

R4

R3

R3
R2

OH

CH3SO3H

R2

R2

R2

R2
R1

Acetic acid

R1

Reflux

R1

O
2

Scheme 1. Synthesis of Flavanone by using Methane Sulphonic


Acid Catalyst
Table 1. Effect of Solvent on Cyclization of 2-Hydroxychalcone to
Flavanone Catalyzed by Methane Sulphonic Acida

Sr.No.

Solvent

Temperature

% Yieldb

1
2
3
4

Acetic acid
Ethanol
DMF
DMSO

110
70
140
140

89
50
40
No Reaction

Reaction Condition:
Sulphonic Acid

All purchased chemicals were of analytical grade and used


without further purification. Melting point is determined
by open capillary method and uncorrected. The 1H NMR
spectra were obtained on a Bruker DRX-300 Avance
instrument using CDCl3 as solvent and TMS as internal
standard at 300MHz.

by

3. Results and Discussion

2. Experimental

ISSN 2049-954X

2-hydroxychalcone

(1mmole),

Methane

(10% v/v) in Solvent : Isolated Yield

Further the scope of the reaction was studied with


substituted chalcones prepared by varying the substrates on
B ring from electron donating groups to withdrawing
groups. The results are presented in Table 2. As obvious
from the results, the Cyclization of chalcones proceeds
well to afford flavanones in good yield. As expected
electron donating groups facilitate the cyclization to afford
the corresponding flavanone in good yield while electron
withdrawing groups and steric effects render the
cyclization slow leading to moderate yield of flavanone. In
next step the scope of reaction was examined by subjecting
substituted ring A chalcone with 5-hydroxy, 7-hydroxy,
5,7-dihydroxy which undergo cyclization easily, giving
good yields of corresponding flavanones. By using this

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P. Zubaidha et al / Chemistry Journal (2012), Vol. 02, Issue 03, pp. 106-110

methodology we have synthesised 5-hydroxyflavanone, 4chloro-7-hydroxyflav-anone, 4-methoxy-7-hydroxyflavanone, 5,7-dihydroxyfla-vanone, and 4-methoxy-5,7-hydroxyflavanone.

ISSN 2049-954X

A possible reaction mechanism for the intramolecular oxaMichael addition in 1a, promoted by Bronsted acid, as
given by Johnsons group, is outlined in Scheme 2 (Ellis et
al, 1982 and 1983). The carbonyl oxygen of 1a accepts

Table 2. Cyclization of 2-Hydroxy Chalcone to Flavanone Catalyzed by Methane Sulphonic Acida

Entry

Chalcone (1)

R1

R2

R3

R4

R5

R6

Flavanone (2)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23

1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w

H
H
H
H
H
H
H
H
H
H
H
H
OH
OH
H
H
H
H
H
H
H
OH
OH

H
H
H
H
H
H
H
H
H
H
H
H
OH
H
H
OH
OH
H
H
H
H
H
OH

H
H
H
H
H
H
OMe
CH3
Cl
H
Cl
H
H
H
H
H
H
H
H
H
OMe
H
H

H
OMe
H
H
OMe
OMe
H
H
H
H
H
H
H
H
NO2
H
H
H
OMe
H
OMe
OMe
H

H
OMe
Cl
CH3
H
H
H
H
Cl
Br
H
F
H
Cl
H
OMe
Cl
OMe
OMe
NO2
H
OMe
OMe

H
OMe
H
H
H
OMe
OMe
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H

2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w

Time
(hrs)
2
1.45
2.30
2.10
2.25
2.15
2
2.40
2.45
2.30
2.30
3
1.5
1.45
1.20
1.05
1.40
1.35
1.50
3.15
3.40
3.50
3.45

%Yield
89
86
82
80
73
78
75
69
65
73
68
82
64
73
79
76
71
85
82
62
76
73
72

Reaction Condition : 2-Hydroxychalcone (1 mmole), Methane Sulphonic Acid (10% v/v) in Solvent b : Isolated Yield

OH

H+

OH

O+

OH
+

OH

+
O

OH

H+

H+

III

OH

OH
II

Scheme 2. Possible Reaction Mechanism in the Presence of Bronsted Acid

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P. Zubaidha et al / Chemistry Journal (2012), Vol. 02, Issue 03, pp. 106-110

proton from the Bronsted acid to give the protonated form


of I and canonical form II undergoes ring closure to give
the enol form III of 2a.

ISSN 2049-954X

sulfonic acid, an environmental friendly acid. J. Mol.


Catalysis A: Chemical, pp. 182-183 and pp. 137-141.
Dauzonne, D., and Monneret, C. (1997) A New Synthesis
of Flavanones. Synthesis, pp. 1305-1308.

4. Conclusion
In conclusion, here in we report simple and an efficient
method for the synthesis of flavanone from 2hydroxychalcone by the use of methane sulphonic acid an
inexpensive and safe acid catalyst. This protocol will be a
good addition to the most recent environmentally friendly
methods reported for the synthesis of flavanones. This
protocol is also useful for the synthesis of phloroglucinol
type flavanone. Other advantages of this method are high
yield and shorter reaction time compare to other reaction
conditions. Merits of this method over trifluroacetic acid
and mineral acid are that 1) this acid is biodegradable and
can be recycled while trifluroacetic acid is not
biodegradable 2) example reported with trifluroacetic acid
includes only methoxy group while this method is
applicable to all types of functional groups.

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