A simple and highly efficient method for the synthesis of chalcones by using borontrifluoride-etherate

Article abstract of DOI:10.1016/j.tetlet.2007.03.054

Chalcones are secondary metabolites of terrestrial plants, precursors for the biosynthesis of flavonoids and exhibit various biological activities. Condensation of substituted acetophenones (2a-12a) with various aromatic aldehydes (1b-7b) in the presence of BF₃-Et₂O at room temperature gave chalcones in 75-96% yield.

Full text of DOI:10.1016/j.tetlet.2007.03.054

Tetrahedron Letters 48 (2007) 3177–3180
A simple and highly efficient method for the synthesis of
I
chalcones by using borontrifluoride-etherate
*
T. Narender and K. Papi Reddy
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 14 February 2007; revised 2 March 2007; accepted 8 March 2007
Available online 12 March 2007
Abstract—Chalcones are secondary metabolites of terrestrial plants, precursors for the biosynthesis of flavonoids and exhibit
various biological activities. Condensation of substituted acetophenones (2a–12a) with various aromatic aldehydes (1b–7b) in the
3 2
presence of BF –Et O at room temperature gave chalcones in 75–96% yield.
ꢀ
2007 Published by Elsevier Ltd.
Chalcones are the main precursors for the biosynthesis
of flavonoids, which are frequent components of the
human diet. Licochalcone A isolated from the roots of
Glycyrrhiza inflata (licorice) has in vitro and in vivo anti-
OH
OH
O
1
2
HO
OCH3
malarial and antileishmanial activity, 3-methoxy-4-
hydroxyloncocarpin isolated from the roots of Loncho-
carpus utilis inhibits NADH:ubiquinone oxidoreductase
OCH3
OH
O
3
O
activity and synthetic chalcones such as 2,4-dimethoxy-
0
0
Licochalcone A
3-methoxy-4-hydroxyloncocarpin
4
-allyloxychalcone and 2,4-dimethoxy-4 -butoxychal-
OCH3
4
OCH3
cone have been reported as antileishmanial agents
(
Fig. 1). Recent studies on biological evaluation of chal-
O
O
5
cones revealed some to be anti-cancer, anti-inflamma-
tory, antimitotic, anti-tubercular, cardiovascular,
OCH3
OCH3
6
7
8
9
1
0
O
cell differentiation inducing, nitric oxide regulation
O
11
modulatory and anti-hyperglycemic agents.12
2,4-dimethoxy-4'-allylchalcone
2,4-dimethoxy-4'-butoxychalcone
Figure 1. Naturally occurring chalcones (licochalcone A and 3-
Of the many methods available for the synthesis of
chalcones, the most widely used is the base catalysed
Claisen–Schmidt reaction in which the condensation
of a ketone with an aldehyde is carried out in the
methoxy-4-hydroxyloncocarpin) and synthetic chalcones (2,4-dime-
0
0
thoxy-4 -allyloxychalcone and 2,4-dimethoxy-4 -butoxychalcone).
and Hauser25 described the use of BF gas for one exam-
1
3
14
15
3
presence of aq NaOH, KOH, Ba(OH)2, hydrotal-
ple, the condensation of acetophenone with benzalde-
hyde. This method has several disadvantages such as
cites,1 LiHDMS and calcined NaNO /natural phos-
6
17
3
1
8
phates. The acid catalyzed methodologies include the
use of AlCl3, dry HCl, Zn(bpy)(OAc) , TiCl4,
Cp ZrH /NiCl , Zeolites and RuCl3.
the special efforts needed to pass BF gas into the reac-
1
9
20
21
22
3
2
tion mixture (commercial BF gas was passed through a
2
3
16
24
3
2
2
2
solution of boric oxide in concd H SO to remove
2
4
hydrogen fluoride), or a special experimental set up for
BF gas generation, the high cost of BF gas and a labo-
rious work-up.
To our knowledge, BF –Et O has not been used for the
Claisen–Schmidt reaction, however in 1940, Breslow
3
2
3
3
To generalize our methodology we synthesized several
chalcones 1c–15c (Table 1) by reacting various substi-
tuted acetophenones (2a–12a) and substituted benz-
aldehydes (1b–7b) using 0.5 equiv of BF –Et O
3 2
Keywords: Chalcone; Synthesis; BF –Et O; Claisen–Schmidt reaction.
q
This is CDRI Communication No. 7138.
*
Corresponding author. Tel.: +91 522 2612411 17; fax: +91 522
2623405; e-mail: tnarender@rediffmail.com
3
2
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.03.054

3
178
T. Narender, K. Papi Reddy / Tetrahedron Letters 48 (2007) 3177–3180
–Et
Table 1. Synthetic chalcones (1c–15c) prepared using BF
3
2
O
a
Entry
Ketone
Aldehyde
Chalcone (product)
Time (min)
Yield (%)
Mp (ꢁC)
O
OMe
OMe
OMe
1
30
94
85–87
O
OMe
H
H
1
a
2
1
c
O
O
1
b
2
3
4
5
6
15
90
80
87
93
96
56–57
a
O
2
b
O
2c
OH
HO
HO
OH
H
150
90
196–198
168–170
197–198
160–162
3
a O
O
3b
3
c
O
AcO
AcO
OH
OH
H
H
4
a
O
O
O
O
3b
4b
3b
O
4c
AcHN
OMe
AcHN
OMe
90
5
a
O
O
5
c
OH
O
OH
O
H
120
6
a
O
O
6
c
O N
2
O N
2
HO
7
8
H
150
60
93
92
187–189
192–194
HO
7
a
O
O
5
b
O
7
c
O N
OMe
2
O N
OMe
2
H
8
a
O
O
4b
O
8
c
MeO
MeO
O N
2
O N
2
9
H
30
88
90
128–130
194–196
OMe
O
O
5b
MeO
O
9
a
9c
HO
OMe
OMe
HO
OMe
OMe
F
OMe
1
1
1
0
1
2
150
H
H
H
3
a
O
O
O
O
1b
O
1
0c
Cl
OMe
OMe
OMe
Cl
150
90
75
81
134–136
130–132
Cl
O
1
0a
Cl
O
1
b
1
1c
F
MeO
F
MeO
F
OMe
O
9
a
6b
MeO
O
1
2c

T. Narender, K. Papi Reddy / Tetrahedron Letters 48 (2007) 3177–3180
3179
Table 1 (continued)
Entry Ketone
a
Aldehyde
Chalcone (product)
Time (min)
150
Yield (%)
Mp (ꢁC)
F
OMe
F
OMe
13
82
97–99
H
O
F
O
O
4b
1
1a
O
13c
Cl
Cl
H
H
HO
1
1
4
5
30
60
87
92
148–150
HO
7
a
O
7
b
O
14c
OMe
OMe
OMe
C16H33
O
OMe
C16H33
O
Oil
O
1
2a
O
O
1
b
15c
a
Isolated yields.
O
OH
O
OH
BF3-Et2O
O
+
O
H
Dioxane 87%
rt, 90 min
4
c
O
O
3b
4b
4a
O
O
OMe
H
N
OMe
HN
BF3-Et2O
O
+
H
Dioxane 93%
rt, 90 min
O
O
5c
O
5a
3 2
Scheme 1. Synthesis of O-acylated and N-acylated chalcones by using BF –Et O.
(
1
Scheme 1).26 Most of the products were formed within
5–150 min and the trans double bond was obtained
work-up, short reaction times, no side reactions, no col-
umn-chromatography in most cases, a convenient
exclusively. The reaction mixture was washed with water
source of BF , solvent-free reactions in the case of liquid
3
to remove BF complexes, concentrated and recrystal-
lized to give pure chalcones (1c–15c) in high yields with-
reactants and tolerance of base sensitive functional
groups (esters, amides).
3
out column chromatography in most cases.
Acknowledgements
In aq KOH or NaOH assisted reactions, reaction times
were much longer (2–4 days), with high probability of
side reactions such as the Cannizzaro reaction or aldol
condensation. By using BF –Et O we obtained chal-
cones exclusively, within 15–150 min and moreover, we
did not observe any side reactions.
The authors are grateful to the Director, CDRI, Luc-
know, India for the drug development programme on
antimalarial and antileishmanial agents, SAIF for spec-
tral data. K.P.R. thanks the CSIR, New Delhi for the
award of an SR fellowship.
3
2
It is important to note that BF –Et O can be used in the
3
2
presence of ester and amide functional groups. To dem-
onstrate this we carried out a condensation reaction be-
tween O-acylated 4a or N-acylated acetophenone 5a and
aromatic aldehydes (3b, 4b) and synthesized O-acylated
Supplementary data
Spectral data of all the synthetic compounds are avail-
able in the supplementary data. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.03.054.
4
c or N-acylated chalcones 5c in high yields (Scheme 1)
by using BF –Et O. These types of reactions cannot be
3
2
carried out using KOH or NaOH since hydrolysis of
the ester or amide would occur.
References and notes
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3180
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1
3 2
BF –Et O (0.6 mL, 5 mmol) at room temperature. (If the
reactants were solids, a little dry dioxane was used as a
solvent). The solution was stirred for 15 min at room
temperature. After dilution with moist ether (100 mL), the
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2
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the colour and the BF
solution obtained after extraction was dried over anhyd.
Na SO and evaporated under reduced pressure. The crude
3 2
–Et O complex. The ethereal
2
4
mixture was passed through a silica gel column chroma-
tography to afford desired chalcone 2c (1.85 g, 90%).