One pot synthesis of aryl substituted aurones

Article abstract of DOI:10.1016/j.dyepig.2011.05.026

An efficient one-pot synthesis of new 4-hydroxy-2-(diarylmethylene) benzofuran-3(2H)-ones dyes (aryl substituted aurones) from 2′,6′- dihydroxyacetophenone, potassium tert-butoxide and aromatic ketones under thermal conditions is described.

Full text of DOI:10.1016/j.dyepig.2011.05.026

Dyes and Pigments 92 (2011) 537e541
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Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
One pot synthesis of aryl substituted aurones
,
b
b
a
Céu M. Sousa a , Jérôme Berthet , Stephanie Delbaere , Paulo J. Coelho
*
a Centro de Química e Vila Real, Universidade de Trás-os-Montes e Alto Douro, Quinta dos Prados, 5001-801 Vila Real, Portugal
b Université Lille Nord de France, CNRS UMR 8516, UDSL, Faculté des Sciences Pharmaceutiques et Biologiques, F-59006 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot synthesis of new 4-hydroxy-2-(diarylmethylene)benzofuran-3(2H)-ones dyes (aryl
substituted aurones) from 20,60-dihydroxyacetophenone, potassium tert-butoxide and aromatic ketones
under thermal conditions is described.
Received 28 February 2011
Received in revised form
27 May 2011
Accepted 31 May 2011
Available online 6 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aurone
Benzofuranone
Dyes
20,60-Dihydroxyacetophenone
Benzophenone
9-Fluorenone
O
1. Introduction
Aurones (2-benzylidenebenzofuran-3(2H)-ones) are natural
occurring yellow dyes found especially in plants and in some
marine organisms, usually in a hydroxylated form. Both E and Z
isomers can be found in nature, although the latter is thermo-
dynamically more stable and thus much more abundant. Besides
their contribution to the pigmentation of flowers and fruits [1]
aurones exhibit a wide variety of biological activities: they have
been described as antifungal agents [2e4], antibacterial agents
[5e9], insect antifeedant agents [10], antioxidants [11e14], as
inhibitors of tyrosinase [15], iodothyronine-deiodinase [16],
acetylcholinesterase [17], anticancer [18e20] and as possessing
anti-inflammatory properties [10]. These compounds are usually
prepared by three main methods: condensation between ben-
zofuranones and benzaldehydes [10,15,17,18,21,22], oxidative
cyclisation of 20-hydroxychalcones [11] or by catalysed cyclisation
of ortho-(1-hydroxyprop-2-ynyl)phenols or ortho-hydroxyaryl
arylethynyl ketones [23e25]. In this paper we describe a fast and
easy one-pot synthesis of new aryl substituted aurones starting
from commercially available materials under thermal conditions.
O
(Z)-Aurone
2. Results and discussion
20-Hydroxychalcones can be easily prepared, under mild condi-
tions, by aldol condensation between 20-hydroxyacetophenone and
different benzaldehydes in the presence of base. This reaction is very
general and these compounds are valuable intermediates in the
synthesis of flavones [26e28] and aurones [11] (Scheme 1).
The reaction of 20-hydroxyacetophenone with benzophenone in
the presence of t-BuOK in toluene at reflux, gives the expected aryl
substituted 20-hydroxychalcone an useful compound that can be
converted in acid medium to the 2,2-diphenylchroman-1-one, an
important precursor for the synthesis photochromic chromenes
[29,30]. In an attempt to prepare 20,60-dihydroxy-3-phenylchalcone
we tried the reaction of 20,60-dihydroxyacetophenone with benzo-
phenone in the presence of t-BuOK and using toluene as solvent, but
no reaction was detected after 8 h at reflux. Changing the solvent to
xylene led to the same result while when the reaction was performed
in high boiling point solvents like DMSO, ethyleneglycol or nitro-
benzene only degradation products were observed (Scheme 2).
* Corresponding author. Tel.: þ351 259 350284; fax: þ351 259 350480.
E-mail address: pcoelho@utad.pt (C.M. Sousa).
0143-7208/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.dyepig.2011.05.026

538
C.M. Sousa et al. / Dyes and Pigments 92 (2011) 537e541
O
O
Flavone
Aurone
I2
OH
O
OH
O
O
DMSO
Base
H
+
Hg(OAc)2
O
Chalcone
Pyridine
O
Scheme 1. Synthesis of flavones and aurones from 20-hydroxychalcones.
OH
O
OH
O
O
OH
O
OH
No reaction
t-BuOK
t-BuOK
Toluene, reflux
Toluene, reflux
Scheme 2. Reaction of 20-hydroxyacetophenone and 20,60-dihydroxyacetophenone with benzophenone.
However, heating a mixture of 20,60-dihydroxyacetophenone,
potassium tert-butoxide and benzophenone in the presence of
a very small amount of DMSO at 200 ꢀC for 2 min affords a red mass
that upon acid hydrolysis originated a deep yellow dye.
The dye 1a was obtained in 10% yield after column chroma-
tography. Heating the reaction mixture for more than 2 min, or at
higher temperature leads to more degradation while heating at
lower temperature, leaves too much unreactive material. The
reaction also works using t-butanol or DMF as solvent but with
lower yields (7 and 8%, respectively) and the amount of solvent
must be very low. If several mL are used only degradation products
are detected. The best results were obtained using 60 mg of DMSO
for 0.5 mmol of 20,60-dihydroxyacetophenone. Heating the reagents
in an inert atmosphere (N2) gave the same result.
The 1H NMR spectrum of this compound showed the expected
aromatic signals but the absence of any signal that could be
attributed to ethylenic protons, and the presence of only one
phenolic proton pointed to a different structure. Mass spectrometry
confirmed the molecular formula of the product as C21H14O3 which
indicates a difference of two hydrogen atoms from the predicted
chalcone structure.
The structure of this new yellow dye was unambiguously
established using 2D NMR experiments as being an aurone deri-
vative (Scheme 3). 1He1H scalar correlations were measured in
COSY experiment (Fig. 1) from H-5 at 6.60 ppm up to H-7 at
6.76 ppm via H-6 at 7.51 ppm and for the two phenyl groups
between H-30/70 at 7.60 ppm and H-40/60 at 7.44 ppm, and between
H-90/130 at 7.37 ppm and H-100/120 at 7.50 ppm.
The HMBC spectrum (Fig. 2) evidences long-range CeH corre-
lations between carbon Ce4 at 156.9 ppm and aromatic protons
H-5, H-6 and H-7, and the phenolic function at 8.06 ppm. The fur-
anone quaternary carbons C-7a and C-3 were evidenced at
163.8 ppm and 184.8 ppm, respectively. Carbon C-7a is long-range
correlated with H-5, H-6 and H-7, while carbon C-3 is correlated
with H-5 and H-7. The carbon C-10 at 133.0 ppm is long-range
correlated with H-30/70 and H-90/130.
5'
4'
OH
O
OH
4
O
6'
3'
O
3a
t-BuOK, DMSO
2'
7'
9'
5
3
1'
8'
2
+
200ºC
6
O
7a
OH
7
10'
13'
1a
11'
12'
Scheme 3. Synthesis of 4-hydroxy-2-(diphenylmethylene)benzofuran-3(2H)-one
dye 1a.
Fig. 1. 1He1H COSY of 1a in CDCl3.

C.M. Sousa et al. / Dyes and Pigments 92 (2011) 537e541
539
The mechanism of this reaction may involve the intermediate
formation of the chalcone by aldol condensation followed by
intramolecular nucleophilic addition to the conjugated double
bond leading to a carbanion stabilised by the two aromatic
substituents, and finally dehydrogenation under thermal condi-
tions leading to the conjugated aurone 1a (Scheme 4).
Starting from fluorenone or 2-hydroxyfluorenone we obtained
new 4-hydroxy-2-(diarylmethylene)benzofuran-3(2H)-ones dyes
(aryl substituted aurones) 1b and 1c in 9 and 8% yield, respectively
(Table 1). Although the yields of this transformation are rather low
(8-10%), this reaction gives rise in one-pot to rather complex
molecules that are not easy to prepare by other methods. To our
knowledge there is only one report concerning the synthesis of
2-(diarylmethylene)-3-benzofuranones, in 4 steps from commer-
cially available compounds [24].
The complete assignments of all proton and carbon resonances
for dyes 1aec is reported in Table 2. For aurone 1c the higher
chemical shift of proton H-30 (8.89 ppm), relative to proton H-130
(8.36 ppm), suggests the position of the former near the carbonyl
group. To unambiguously establish the configuration of the double
bond of this compound, a 1D-NOESY experiment was performed
(Fig. 3). Since a strong dipolar correlation between H-130 at
8.36 ppm and H-7 at 6.98 ppm and H-120 at 7.15 ppm was observed,
proton H-130 must be on the same side of H-7 and therefore the
double bond has an E configuration.
Fig. 2. 1He13C HMBC of 1a in CDCl3.
These dyes show a broad absorption band in the UVeVis spec-
trum with a maximum between 398e435 nm and molar absorp-
tion coefficients (
e
) of 0.9 ꢁ 104 to 1.5 ꢁ104 Mꢂ1 cmꢂ1 in CH2Cl2
OH
O
Ph
OH
OH
O
O
O
O
Ph
O
OH
OH
O
O
Ph
+
Ph
Ph
Ph
OH
OH
OH
O
O
O
OH
H Ph
Ph
H H
Ph
Ph
Ph
Ph
Dehydrogenation
O
O
O
Scheme 4. Proposed mechanism for the formation of 4-hydroxy-2-(diphenylmethylene)benzofuran-3(2H)-one dye 1a.
Table 1
Synthesis of 4-hydroxy-2-(diarylmethylene)benzofuran-3(2H)-ones dyes.
λmax
λmax in basic
Ketone
Product
Yield (%)
10
medium (nm)
(nm) (ε)
O
OH
O
398 (9 x 103)
435 (1.5 x 104)
433 (4.6 x 104)
462
519
500
O
1a
O
O
OH
O
9
8
O
1b
OH
1c
HO
OH
O
O

540
C.M. Sousa et al. / Dyes and Pigments 92 (2011) 537e541
Table 2
0.7
aurone 1b
addition of base (NBu4OH)
435
NMR spectral data for dyes 1aec.
Dye 1a (CDCl3)
1b in CDCl3
1c in DMSO-d6
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1H
13C
1H
13C
1H
13C
519
2
3
3a
4
5
e
143.6
184.8
110.8
156.9
109.3
139.0
103.2
163.8
133.0
137.1
131.4
128.3
129.6
128.3
131.4
135.4
130.5
128.3
129.1
128.3
130.5
e
e
146.3
186.3
110.4
157.3
109.9
139.4
103.3
163.7
129.4
135.3
128.0
128.0
130.8
119.9
141.3
137.0
142.2
119.9
130.8
128.0
129.5
e
e
147.0
182.2
110.6
157.9
111.1
139.3
102.8
165.0
125.6
136.5
115.5
158.5
117.5
121.5
132.5
136.7
142.0
119.6
130.9
127.0
129.0
e
e
e
e
e
e
e
e
e
e
6.60
7.51
6.76
e
6.69
7.59
6.88
e
6.69
7.61
6.98
e
6
7
7a
10
e
e
e
20
e
e
e
30
7.60
7.44
7.44
7.44
7.60
e
9.33
7.37
7.44
7.68
e
8.89
e
300
400
500
600
700
40
50
6.86
7.65
Wavelength (nm)
60
Fig. 4. UV/Vis spectra of compound 1b (4.3 ꢁ 10ꢂ5 M, CH2Cl2) before and after the
70
e
80
e
e
addition of base (Bu4NOH).
90
7.37
7.50
7.50
7.50
7.37
8.06
e
e
100
110
120
130
OH
7.68
7.44
7.37
8.46
8.32
7.69
7.41
7.29
8.36
11.26 (C-4)
9.71 (C-40)
which are in the range of those reported in the literature for
aurones [31]. Since these aurones have phenolic groups their
absorption spectra is pH dependent. The addition of base (Bu4NOH)
leads, as expected, to a strong bathochromic shift of the lmax
(64e84 nm) due to the formation of the phenolate anion (Fig. 4).
J in Hz
7.8
J in Hz
7.6
7.4
J in Hz
8.6
30e40
40e50
50e60
7.2
3. Experimental
60e70
7.8
7.8
90e100
100e110
110e120
120e130
5e6
The reactions were monitored by thin-layer chromatography on
aluminum plates precoated with Merck silica gel 60 F254
(0.25 mm). Melting point were determined in capillary tubes and
are uncorrected. The new compounds were determined to be >95%
pure by 1H NMR spectroscopy. UVeVis spectra were recorded on
a CARY 50 Varian spectrophotometer. IR spectra were obtained on
a PerkineElmer FTIR 1600 spectrometer using KBr disks (wave-
numbers in cmꢂ1). Electronic impact mass spectra were measured
7.2
7.4
8.1
8.3
8.2
7.4
7.7
7.8
8.2
8.2
2.2
7.8
8.0
8.0
6e7
30e50
HO
4'
5'
OH
3'
O
6'
4
2'
1'
8'
13'
3a
5
3
7'
9'
2
6
7a
O
10'
11'
7
12'
3
6
6
5
7
11
13
12
5
10
OH-
OH-4 (Broad
a
b
12
7
13
11
10
9
8
[ppm]
1
Fig. 3. a) H NMR spectrum of 1c and b) 1D NOESY spectrum with an irradiation of H-130 to observe dipolar correlation.

C.M. Sousa et al. / Dyes and Pigments 92 (2011) 537e541
541
on a AutoSpecE spectrometer. The 1H and 13C NMR spectra were
recorded at 298 K in CDCl3 or DMSO using a Bruker Avance-500
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499e505.
spectrometer. Chemical shifts (d) were reported in ppm and
coupling constants (J) in Hz. Heteronuclear 1He13C HSQC and
HMBC experiments were carried out using standard procedures.
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3.1. 4-Hydroxy-2-(diphenylmethylene)benzofuran-3(2H)-one 1a
20,60-dihydroxyacetophenone (76 mg, 0.5 mmol), potassium tert-
butoxide (168 mg,1.5 mmol), benzophenone (182 mg,1.0 mmol) and
DMSO (60 mg) were mixed to get an homogeneous mass and heated
in an oil bath at 200 ꢀC for 2 min. The red-dark mass was hydrolysed
with HCl (30 mL, 5%) and the mixture extracted with diethyl ether
(3 ꢁ 20 mL). The yellow-orange organic phase was extracted with
NaOH (10%, 20 mL) and the aqueous phase discarded. 20 mL of HCl
(10%) were added and the mixture shaken vigorously. Finally the
organic phase was separated, dried over anhydrous sodium sulphate
and evaporated to give an yellow oil that was purified by column
chromatography on SiO2 (2e5% EtOAc/Petroleum ether) to afford dye
1a as an yellow solid (16 mg, 10% yield). mp 117e119 ꢀC. IR: 3157,
3064, 1674, 1614, 1580, 1458, 1300, 1184, 1048. For 1H NMR and
13C NMR data see Table 1. MS: m/z (%):314 (Mþ, 62), 313 (100), 237 (5),
165 (15). Exact mass for C21H14O3: 314.0947; Found 314.0943.
A
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derivatives. Bioorg Med Chem Lett 2007;17(22):6354e63.
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marine brown alga Spatoglossum variabile. Tetrahedron 2007;63(29):6909e14.
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activity of 30,40,6,7-tetrahydroxyaurone, a metabolite of Bidens frondosa. Biosci
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3.2. 2-(9H-Fluoren-9-ylidene)-4-hydroxybenzofuran-3(2H)-one 1b
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Prepared from 9-fluorenone using the same procedure. The
compound 1b was isolated as a yellow solid (14 mg, 9% yield). mp
245-246. IR: 3337, 3106, 3050, 1680, 1636, 1610, 1585, 1467, 1448,
1347, 1318, 1140, 1045. For 1H NMR and 13C NMR data see Table 1.
MS: m/z (%): 312 (Mþ, 6.3), 311 (9), 256 (9), 213 (13), 98 (100). Exact
mass for C21H12O3: 312.0786; Found 312.0780.
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(breast cancer resistance protein). Eur J Pharm Sci 2008;35:293e306.
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agents. Bioorg Med Chem Lett 2003;13(21):3759e63.
3.3. (E)-4-Hydroxy-2-(2-hydroxy-9H-fluoren-9-ylidene)
benzofuran-3(2H)-one 1c
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activity of novel chromone and aurone derivatives. Bioorg Med Chem 2007;
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Prepared from 2-hydroxyfluorenone using 2.5 mmol of potas-
sium tert-butoxide (5 eq). The compound 1c was isolated as an
orange solid (15 mg, 8% yield). mp 220e222. IR: 3470, 3060, 1674,
1639,1617, 1581,1453,1443, 1302, 1263, 1135, 1048. For 1H NMR and
13C NMR data see Table 1. MS: m/z (%): Exact mass for C21H12O4:
328.0736; Found 328.0726.
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Acknowledgements
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To FCT (Portugal’s Foundation for Science and Technology)
and FEDER for financial support through the research unit Centro
de Química-Vila Real (POCTI-SFA-3-616) and project PTDC/QUI/
66012/2006. The 500 MHz NMR facilities were funded by the
Région Nord-Pas de Calais (France), the Ministère de la Jeunesse de
l’Education Nationale et de la Recherche (MJENR) and the Fonds
Européens de Développement Régional (FEDER).
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Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.dyepig.2011.05.026.
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