Green synthesis of novel chalcone and coumarin derivatives via Suzuki coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2012.03.079

Chalcones and coumarins are important naturally occurring plant constituents and display a wide range of pharmacological and biological activities. In an environmentally benign approach, synthesis of biphenyl chalcone and coumarin derivatives was successfully accomplished via Suzuki coupling by using PEG-400 as a solvent under microwave irradiation. Salient feature of this methodology includes: short reaction time, good to excellent yields, and prominent tolerance of different functional groups.

Full text of DOI:10.1016/j.tetlet.2012.03.079

Tetrahedron Letters 53 (2012) 2715–2718
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Green synthesis of novel chalcone and coumarin derivatives via Suzuki
coupling reaction
⇑
Lucas C.C. Vieira, Márcio Weber Paixão, Arlene G. Corrêa
Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Chalcones and coumarins are important naturally occurring plant constituents and display a wide range
of pharmacological and biological activities. In an environmentally benign approach, synthesis of biphe-
nyl chalcone and coumarin derivatives was successfully accomplished via Suzuki coupling by using PEG-
400 as a solvent under microwave irradiation. Salient feature of this methodology includes: short reac-
tion time, good to excellent yields, and prominent tolerance of different functional groups.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 February 2012
Revised 8 March 2012
Accepted 20 March 2012
Available online 29 March 2012
Keywords:
Suzuki reaction
Chalcone
Coumarin
Microwaves
Green technology
Chalcones and coumarins are important naturally occurring
plant constituents and display a wide range of pharmacological
and biological activities,1 such as, anti-inflammatory,2 antibacte-
rial,3 antiviral,4 and antitumoral,5 among others.6 In synthetic per-
spective, chalcone and coumarin derivatives are gaining more
prominence due to their pivotal role in the organic synthesis. How-
ever, only few methods have been already reported on derivatiza-
tion of flavonoids, especially chalcones under Suzuki cross-
coupling conditions.7
Substantial number of reports appeared in the literature for the
synthesis of 3, 4, 6, and 7-substituted coumarins by Suzuki cou-
pling,8 but none for the 8-substituted coumarins. Moreover, these
methodologies usually employ conventional organic solvents, for
example, toluene, acetonitrile, and dichloromethane,9 expensive,
and unstable catalysts such as Pd(PPh3)4 and Pd(dppf)Cl2,10 with
an elevated temperature and reflux for several hours.11 Besides,
green Suzuki coupling reactions have been well accomplished for
simple substrates but not for the densely functionalized sub-
strates.12 Thus, there is still considerable interest in the develop-
ment of highly efficient methods for the synthesis of substituted
chalcones and coumarins.
(PEG) as a solvent. Furthermore, the reaction conditions employed
include an economically cheap and stable catalyst, Pd(OAc)2,
microwave irradiation as a source of energy, in short reaction time,
contemplating the principles of green chemistry.
Chalcones 1a–e (Scheme 1) were synthesized via Claisen–Smith
condensation reaction with 3,4-substituted benzaldehyde and an
aromatic acetophenone, aqueous KOH (50% w/v) in methanol, at
room temperature for 3 h.13 After completion of the reaction, the
mixture was filtered to collect the precipitates and purification by
recrystallization affords the pure chalcones 1a–e in 62–95% yield.
The coupling of compound 1a and phenylboronic acid was cho-
sen as the model reaction for the optimization. Initially, the reac-
tion was carried out in a 3:1 mixture of PEG-400/H2O in the
presence of K2CO3 (3 equiv), Pd(OAc)2 (10 mol %) at 110 °C for
30 min, under microwave irradiation (Table 1, entry 1). The reac-
tion proceeds, however the desired product 2a was delivered in
only 34% yield. Different Pd sources were then examined, and
Pd(OAc)2 was found to be the most effective catalyst (Table 1, entry
3). Among the bases screened, K2CO3 and Cs2CO3, promote the
reaction in moderate yields (Table 1, entries 1 and 5). Having KF
as base the desired product could be obtained in good yield (Ta-
ble 1, entry 6).
On account of these aspects, herein we report an eco-friendly,
efficient, and versatile approach for the synthesis of Suzuki cou-
pling reaction of chalcones and coumarins with arylboronic acids
with low catalyst loading using non-toxic polyethyleneglycol
The influence of solvent system was further evaluated. To our de-
light, by using 3:1 mixture of PEG-400/EtOH as solvent, excellent
yield was achieved (92%, Table 1, entry 8). While other solvents such
as PEG-400 and PEG-400/H2O furnished the desired arylated prod-
uct in moderate yields. Regarding the influence of the solvent in this
coupling reaction, optimal results were achieved using a mixture of
⇑
Corresponding author. Tel.: +55 16 33518281; fax: +55 16 33518350.
E-mail address: agcorrea@ufscar.br (A.G. Corrêa).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.079

2716
L. C. C. Vieira et al. / Tetrahedron Letters 53 (2012) 2715–2718
R1
O
O
R1
O
50% KOH(aq)
MeOH, r.t, 3h.
R2
R3
R5
R6
R2
R3
R5
R6
H
+
R4
R4
1a-e
Yield (%)
95
92
90
83
62
1a: R1=H, R2=H, R3=Br, R4=H, R5=R6=OCH2O
1b: R1=H, R2=R3=OCH2O, R4=H, R5=H, R6=Br
1c:
R1=H, R2=H, R3=Br, R4=H, R5=H, R6=OCH3
1d: R1=H, R2=H, R3=Br, R4=H, R5=H, R6=H
1e: R1=OH, R2=I, R3=OCH3, R4=OCH3, R5=H, R6=OCH3
Scheme 1. Synthesis of chalcones.
Table 1
Suzuki reaction of chalcone 1a with phenylboronic acid in different conditionsa
O
O
B(OH)2
10 mol% catalyst
O
O
O
O
+
base, solvent
Br
30 min, 110 °C, MW
1a
2a
Entry
Catalyst
PdCl2
Base (3 equiv)
Solventb
Yieldc (%)
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KF
K3PO4
KF
KF
PEG-400:H2O
PEG-400:H2O
PEG-400:H2O
PEG-400:H2O
PEG-400:H2O
PEG-400:H2O
PEG-400:H2O
PEG-400:EtOH
PEG-400
34
41
54
46
48
65
11
92
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
56
10
11
12
KF
KF
KF
PEG-400:EtOH
PEG-400:EtOH
PEG-400:EtOH
89d
88e
78f
a
Reaction conditions: Chalcone (1.0 equiv), PhB(OH)2 (1.5 equiv).
PEG-400 (3 mL) and water or EtOH (1 mL).
Isolated yields.
Reaction performed in 15 min.
Reaction performed in 45 min.
b
c
d
e
f
5 mol % of catalyst.
PEG-400/EtOH (Table 1, entry 8). It can be easily rationalized, once
the use of ethanol instead of water enhances the solubility of re-
agents and thus increased the product yield. It is important to note
that when the amount of catalyst is reduced from 10 to 5 mol %, a
decrease in the yield was observed (Table 1, entry 12).
Initially, we evaluated the Suzuki reaction with phenolic cou-
marin 4 and phenylboronic acid using the standard conditions ap-
plied for chalcones, like 10 mol % of Pd(OAc)2 as catalyst, KF as
base, and PEG-400/EtOH as solvent (Table 3). Gratifyingly, this
reaction indeed proceeded to give compound 5a in excellent yield
(95%). Analyzing Table 3, the reaction proceeded very well both for
electron donating and for electron withdrawing groups attached at
boronic acids affording the corresponding products in good to
excellent yields (5b–f).
In conclusion, a useful general synthetic strategy for biphenyl
chalcones and coumarins was developed starting from substituted
halochalcones and 8-iodocoumarin. A series of new chalcone and
coumarin derivatives were able to be synthesized via Suzuki cou-
pling. This approach allows the introduction of different phenyl
substituents in natural products and analogs employing green con-
ditions, using palladium acetate as catalyst, PEG as solvent under
microwave irradiation. Furthermore, many functional groups with-
standing our standard reaction conditions providing the desired
product in good to excellent yield are one of the most important
features of the present methodology.
With the optimal reaction condition in hands, the scope of this
greener catalytic system was then studied, with various chalcones
and phenylboronic acids as reaction patterns (Table 2). We have
observed that the catalytic system was tolerant to a broad range
of functional groups, such as NO2, OMe, OH, C@C, and C@O. Both
electron-rich and electron-deficient chalcones gave the products
with moderate to high yields, and the reaction was not affected
by the standard reaction conditions. Furthermore, sterically hin-
dered chalcones gave moderate yields (Table 2, entries 17–19).
Encouraged by the results of this eco-friendly catalytic system,
we extended the substrate studies for the cross coupling reaction
of 8-iodocoumarin 4 with various phenylboronic acids. Coumarin
4 was prepared via Knoevenagel condensation of 2-hydroxybenzal-
dehyde14 with diethyl malonate followed by the iodination reac-
tion15 (Scheme 2).

L. C. C. Vieira et al. / Tetrahedron Letters 53 (2012) 2715–2718
2717
Table 2
Suzuki reaction of chalcones with different phenylboronic acidsa
O
R1
R2
B(OH)2
Pd(OAc)2, KF
Coupling product
R"
R'
+
2a-s
PEG-400:EtOH
110 °C, MW
30 min
1a-e
Entry
Chalc.
Prod.
R1
R2
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1d
1d
1e
1e
1e
2a
2b
2c
2d
2e
H
H
NO2
OCH3
F
H
OCH3
H
H
OCH3
F
92
95
94
90
87
94
91
91
95
84
90
91
91
90
81
79
53
50
52
2f
CH3
2g
2hb
2ib
2jb
2kb
2lb
2m
2n
2o
2p
2q
2r
O–CH2–O
O–CH2–O
H
H
NO2
F
CH3
H
H
OCH3
H
OCH3
F
OCH3
H
NO2
H
OCH3
NO2
OCH3
H
OCH3
H
2s
H
a
b
c
Reaction conditions: Chalcone (1.0 equiv), boronic acid (1.5 equiv), base (3 equiv), ethanol (1 mL) and PEG-400 (3 mL).
Reaction performed in 45 min.
Isolated yields.
O
O
O
O
O
i
ii
H
OEt
OEt
HO
OH
HO
O
HO
O
I
3
4
Scheme 2. Synthesis of 8-iodine coumarin. Reagents and conditions: (i) Diethyl malonate, piperidine, rt, 2 h, 97%, (ii) Kl, KlO3, HCl, HAc, rt, 4 h, 88%.
Table 3
Suzuki reaction of coumarin 4 with different phenylboronic acidsa
O
O
R1
R2
B(OH)2
Pd(OAc)2, KF
OEt
+
OEt
PEG-400:EtOH
HO
O
O
HO
O
O
MW, 110 °C, 30 min.
I
4
5a-f
R1
R2
Compound
R1
R2
Yieldb (%)
5a
5b
5c
5d
5e
5f
H
H
NO2
OMe
H
H
OMe
H
H
CH2OH
H
95
85
72
87
78
80
Cl
a
Reaction conditions: Coumarin (1.0 equiv), boronic acid (1.5 equiv), KF (3 equiv), ethanol (1 mL) and PEG-400 (3 mL).
Isolated yields.
b

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L. C. C. Vieira et al. / Tetrahedron Letters 53 (2012) 2715–2718
5. (a) Manuele, M. G.; Ferraro, G.; Arcos, M. L. B.; López, P.; Cremaschi, G.; Anesini,
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Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.03.079.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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