Synthesis of 6-aryl/heteroaryl-4-oxo-4H-chromene-2-carboxylic ethyl ester derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.05.096

The development of new chemical entities represents an important challenge in pharmaceutical industry, being the use of privileged scaffolds for library design and drug discovery a valuable approach. Among the panoply of privileged structures, our researc

Full text of DOI:10.1016/j.tetlet.2016.05.096

Tetrahedron Letters 57 (2016) 3006–3010
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Tetrahedron Letters
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Synthesis of 6-aryl/heteroaryl-4-oxo-4H-chromene-2-carboxylic
ethyl ester derivatives
Carlos Fernandes a, Pedro Soares a, Alexandra Gaspar a, Daniel Martins a, Ligia R. Gomes b,c, John N. Low d,
Fernanda Borges a,
⇑
a CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
b REQUIMTE/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
c FP-ENAS-Faculdade de Ciências de Saúde, Escola Superior de Saúde da UFP, Universidade Fernando Pessoa, Rua Carlos da Maia, 296, P-4200-150 Porto, Portugal
d Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen AB24 3UE, Scotland, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of new chemical entities represents an important challenge in pharmaceutical industry,
being the use of privileged scaffolds for library design and drug discovery a valuable approach. Among
the panoply of privileged structures, our research group has focused its attention on the chromone
(4H-benzopyran-4-one) scaffold due to its chemical versatility and ability to bind to multiple targets.
With this endeavour we report an expedite two-step procedure for the synthesis of novel 6-aryl/hetero-
aryl-4-oxo-4H-chromene-2-carboxylic ethyl ester. The new chromones were synthesized by a C–C Suzuki
cross-coupling microwave-assisted reaction, using Pd(OAc)2 as a catalyst, and a classic Claisen condensa-
tion followed by an intramolecular cyclization process.
Received 26 April 2016
Revised 21 May 2016
Accepted 25 May 2016
Available online 26 May 2016
Keywords:
C–C Suzuki coupling
Heteroaryl-chromone
Microwave irradiation
Claisen condensation
X-ray characterization
Ó 2016 Elsevier Ltd. All rights reserved.
Drug research and development processes have undergone a
dramatic transformation over the past decades. Nevertheless, the
key premise remains the same: to discover innovative drugs new
chemical entities are needed to be found.1 Uncovering drug-like
new chemical entities is a gigantic challenge and to overcome such
hurdles several medicinal chemistry programmes have been
resorted on the so-called privileged structures as they can result
in drug-like libraries.2 Moreover, natural products remain one of
the best sources of drugs and drug lead compounds. The inherent
diversity of natural-product structures have long been an inspira-
tion for the development of ‘natural product-like’ libraries being
natural scaffolds attractive starting points for R&D projects.
Among the panoply of privileged structures,2 our research
group has focused its attention on the chromone (4H-benzopy-
ran-4-one) scaffold. The convincing results obtained for the devel-
opment of monoamine oxidase B inhibitors (IMAO-B)3–5 and
adenosine receptors ligands6,7 based on chromone scaffold stimu-
late to continue the project with the design and synthesis of a
new series of 6-phenylchromone derivatives. The rationale for
the design of the new chromone based library is presented in
Figure 1.
The new biaryl compounds were inspired on the backbone of
flavonoids (natural secondary metabolites), and involve a change
of the position of the exocyclic aromatic nucleus C, which is
attached to the chromone ring A instead of B. The new biarylchro-
mone derivatives will contribute for extending chromone chemical
space and biological applications.
To obtain the novel chromone based compounds a simple syn-
thetic two-step strategy was planned (see Scheme 1). This strategy
encompassed the use of the following reactions: a Claisen conden-
sation followed by an intramolecular cyclization, and a Suzuki
cross coupling reaction. In fact, Suzuki C–C cross-coupling reac-
tions are by now considered robust chemical methodologies used
to synthesize compounds on an industrial scale by the pharmaceu-
tical industry. Moreover, Suzuki reaction is considered a valuable
tool for R&D programmes, namely to attain chemical diversity of
chemical libraries.8 Recent catalyst and methodological develop-
ments have broadened its application enabling to perform simpler,
faster and cheaper approaches, when compared to some well-
known chemical transformations.9,10 Within this context, the syn-
thesis of the biaryl chromone derivative 6-phenyl-2-chromone car-
boxylic acid (Scheme 1, compound 2) was done using the
commercial 6-bromo-2-chromone carboxylic acid (1) as starting
material via a Suzuki C–C cross-coupling reaction following the
procedure of Miyaura et al. with minor modifications (Scheme 1).11
⇑
Corresponding author. Tel.: +351 220402560.
E-mail address: fborges@fc.up.pt (F. Borges).
http://dx.doi.org/10.1016/j.tetlet.2016.05.096
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

C. Fernandes et al. / Tetrahedron Letters 57 (2016) 3006–3010
3007
of the critical points of the approach is related to deciding the right
step to perform the Suzuki coupling reaction (Scheme 2, compound
4). As several works reported the synthesis of 6-hetero/aryl ace-
tophenone derivatives,20–22 a new synthetic route depicted in
Scheme 3 was envisaged. Here, the first step corresponds to the
introduction of the phenyl ring on 50-bromo-20-hydroxyacetophe-
none (4) by Suzuki cross-coupling reaction following the procedure
of Arvela et al. with slight modifications.18 The benzopyran back-
bone is then obtained by a Claisen condensation followed by a
cyclisation process (Scheme 3).
C
O
B
A
O
O
R
O
O
O
Since the discovery of the Suzuki reaction, novel and more effi-
cient air/moisture stable Pd catalysts have been described, such as
those reported in the work of Alonso et al.22 However, our main
goal was the synthesis of a library of novel chromone derivatives,
by a convergent and efficient protocol. The method must have
the benefits of operational simplicity and provide good yields of
the targeted molecules. The building of chemical libraries based
on privileged scaffolds with several points of decoration diversity
play a central role in drug discovery processes. The synthetic
strategies defined to this end must encompass the use of confining
and commercial available reagents.
Therefore, the readily commercially available catalyst Pd(OAc)2
was employed in a MW assisted reaction.15 The pretended biaryl
compound (40) intermediate was obtained in good yield (see
Table 1, entry 1) and used as starting material to obtain ethyl-6-
phenyl-4-oxo-4H-chromene-2-carboxylate (Scheme 3, compound
5) following the methodology previously described.12
Flavonoids
Figure 1. Rational followed for the development of new 6-phenyl-4H-chromen-4-
one based library.
Briefly, 6-bromochromone carboxylic acid (1) was suspended in
THF/K2CO3 (2 M) (10:1) and tetrakis(triphenylphosphonium) pal-
ladium(0) (Pd(PPh3)4, 4 mol %) was added. After stirring 30 min
at room temperature, an equimolar amount of phenyl boronic acid
was added. The reaction mixture was heated in reflux and stirred
for 12 h. The crude material was purified by gradient flash chro-
matography. After a laborious purification process, two main frac-
tions were isolated and characterized by 1H NMR. The first fraction
was identified as the phenyl boronic acid self-coupling product and
the second was the desired, but still impure, chromone (2). Thus,
due to the 6-bromochromone carboxylic acid (1) insolubility con-
straints and reaction purification drawbacks, the same reaction
was performed using another starting material, the ester derivative
ethyl 6-bromo-2-chromone carboxylate (Scheme 2, compound 3).
The ester derivative (3) was obtained in a 60% yield from 50-
bromo-20-hydroxyacetophenone (4), via a Claisen condensation
and subsequent intramolecular cyclisation process, following the
procedure of Hadjeri et al. with minor modifications (Scheme 2,
step A).12,13 Then, a C–C cross coupling reaction was performed,
in the same experimental conditions as described previously, using
Pd(PPh3)4 as catalyst (Scheme 2, step B1).11 After purification, com-
pound (5) was obtained in 35% yield.
After reaction optimization, the versatility of the new synthetic
route was checked using diverse aryl/heteroaryl boronic acid
reagents (Table 1).
All aryl/heteroaryl derivatives were obtained in good yields
(70–82%). It was found that neither the electronic donor/acceptor
properties nor the number of the substituents in the aryl ring of
the boronic acid (Table 1, entries 2–8) affect the course of the C–
C cross coupling reaction. The same conclusion applies for the pres-
ence of a heterocyclic ring, instead of an aryl moiety (Table 1,
entries 9 and 10), In contrast, and as regarding the intramolecular
Claisen condensation and cyclization, it is important to stress that
the presence of particular aryl substituents or heterocyclic rings on
the boronic acids affects the performance of the second step. The
presence of electron donating groups (Table 2, entries 2–4) and
halogens (entries 5–7) lead to an improvement of the reaction
yield, when compared with the aryl unsubstituted counterpart
(Table 2, entry 1). Contrariwise, the presence of strong withdraw-
ing groups (Table 2, entry 8) lead to a decrease of the reaction yield.
The same tendency was observed with the of heteroaryl deriva-
tives (Table 2, entries 9 and 10).
Since the Pd(PPh3)4 catalyst has been reported as having air/-
moisture drawbacks it was decided to perform the C–C cross cou-
pling reaction with Pd(OAc)2 (Scheme 2, step B2).14 However,
compound (5) was obtained in a lower yield (10%). So, in order
to try to improve reaction yield it was decided to use microwave
(MW) irradiation as heating source, once MW heating has been
described as a suitable tool to enhance the performance of C–C
cross coupling reactions.15–17
The reaction was performed following the procedure Arvela
et al. (Scheme 2, step B3),18,19 by which tetrabutylammonium bro-
mide (TBAB), K2CO3 and phenyl boronic acid were added to an
aqueous suspension of the ester (3). After addition of Pd(OAc)2
(0.4 mol %) the system was heated to 150 °C for 15 min in a micro-
wave apparatus. After work-up, purification and 1H NMR analysis,
it was concluded that the intended compound was not obtained.
Along the reaction, the chromone ring opened giving rise to an ace-
tophenone derivative (data not shown).
It is important to highlight that ethyl-6-phenyl-4-oxo-4H-chro-
mene-2-carboxylate (Scheme 2, compound 5) has already been
obtained by Witiak et al.23 Yet, the synthetic strategy was quite dif-
ferent from the one herein reported. Witiak et al.23 used p-
phenylphenol as starting material to attain 5-phenylsalicylic acid,
by a Marasse modified Kolbe–Schmidt reaction, which was then
converted into the desired 2-hydroxy-5-phenylacetophenone by
a direct methylation reaction with MeLi in 1,2-dimethoxethane.
Subsequently, the chromone ester (5) was obtained (63% overall
yield) by a two-step process involving the obtention of a diketo
ester intermediate by a condensation reaction with ethyl oxalate.
The isolated intermediate was subjected to an intramolecular
cyclization by refluxing it in acetic acid containing a catalytic
amount of HCl. Thus, the synthetic strategy here described
(Scheme 2, step A and B1) is less laborious, resourcing to a two-step
methodology and using less harsh conditions.
In fact, the stability of the benzopyrone ring on basic medium5
can be pointed out as a drawback of the synthetic strategy. So, one
O
COOH
O
O
COOH
Pd(PPh3)4
Br
OH
B
O
OH
(1)
(2)
All the chromones were fully characterized by 1H and 13C NMR
and by MS mass spectrometry and several of them structurally
characterized by single crystal X-ray diffractometry24 but however,
Scheme 1. Synthetic strategy used to obtain the 6-phenyl-2-chromone carboxylic
acid (2) by Suzuki cross-coupling reaction.

3008
C. Fernandes et al. / Tetrahedron Letters 57 (2016) 3006–3010
OH
Br
O
(4)
A
1.
2.
oxalate/ NaOEt
Diethyl
HCl
B3
B1
O
COOEt
Br
O
(3)
Pd(PPh3)4
Pd(OAc)2
OH
OH
B
Pd(OAc)2
B
OH
OH
OH
B
B2
OH
MW
O
O
COOEt
(5)
Scheme 2. Synthetic strategies used to obtain ethyl-6-phenyl-4-oxo-4H-chromene-2-carboxylate (5).
MW
OH
O
OH
O
Table 1
Pd(OAc)2
Effect of aryl/heteroaryl boronic acids on the Suzuki cross-coupling reactions
Br
OH
B
OH
OH
OH
R-B(OH)2
(4)
(4')
Br
R
O
O
(4)
1.
oxalate / NaOEt
Diethyl
2. HCl
Entry
1
R =
Yield (%)
74
O
O
COOEt
2
3
4
78
73
79
H
3C
(5)
H
3CO
Scheme 3. Synthetic strategy used for the obtention of ethyl-6-phenyl-4-oxo-4H-
chromene-2-carboxylate (5).
H
3CO
H
3CO
only the molecular and supramolecular structures of ethyl
6-(benzofuran-2-yl)-4-oxo-4H-chromene-2-carboxylate (Table 2,
entry 10) is presented and discussed in this Letter. The ellipsoid
diagram and adopted numbering scheme of this compound is
shown in Figure 2.
The X-ray data confirm that the compound has two heteroaro-
matic moieties viz benzofuran and benzopyran rings, and an ethyl
ester substituent linked to the position 2 of the chromone ring. The
oxygen atom of the pyran ring is –cis related to the carbonyl oxy-
gen atom O21 of the ester substituent. The aromatic rings are vir-
tually planar and the dihedral angle between the mean planes of
the benzofuran moiety and the 10-membered chromone moiety
is 3.54 (3)°. The value for the C62—C6 bond distance (1.464 Å) is
slightly shorter than the expected value for Csp3—Csp3 bond,25
indicating a spread of the electronic cloud within the heteroaro-
matic rings similar to what happens with p-phenylenes. The
planarity of the molecule is broken by a small twist around the
5
6
70
81
Cl
F
F
7
82
F
F
8
9
73
75
O2N
O
10
79
O

C. Fernandes et al. / Tetrahedron Letters 57 (2016) 3006–3010
3009
Table 2
Effect of aryl/heteroaryl acetophenones on the synthesis of chromone ethyl esters
OH
O
COOEt
R
R
O
O
Entry
1
R =
Yield (%)
56
2
3
65
64
H
3C
H
H
3CO
3CO
4
5
6
70
60
69
Figure 3. Supramolecular structure of 6-(benzofuran-2-yl)-4-oxo-4H-chromene-2-
carboxylate.
H
3CO
Cl
ethyl ester derivatives was successfully developed. Moreover, the
reduction of the reaction time, less formation of by-products, and
easier work-up makes this new synthetic strategy suitable for
obtaining analogue-based chemical libraries for medicinal chem-
istry programmes. The methodology herein described proved to
be versatile and a stimulating starting point for the development
of an automated process suitable for the synthesis of a larger
library of new functionalized chromones with drug-like properties.
In addition, X-ray data allow to validate the planarity of this
type of systems a property that can be of utmost importance for
understanding their biological properties as antilipidemic agents.
F
F
7
64
F
F
8
9
44
52
O2N
O
Acknowledgments
10
55
O
This work was supported by the Foundation for Science and
Technology (FCT) of Portugal (UID/QUI/UI0081/2015 and POCI-
01-0145-FEDER-006980). C. Fernandes (SFRH/BD/98519/2013)
and A. Gaspar (SFRH/BPD/93331/2013) grants are supported by
FCT, POPH and QREN.
C2—C21 bond, the best plane formed by the non-hydrogen atoms
of the ethoxy residue makes a dihedral angle of 12.85 (6)° with
the best plane of the 10 membered chromone residue.
The supramolecular structure (Fig. 3) is built by weak C–H. . .O
intramolecular interactions. Specifically, the molecules are linked
by the C22—H22ꢀ ꢀ ꢀO21 (ꢁx + 3/2, y + 1/2, ꢁz + 3/2) and
C63—H63ꢀ ꢀ ꢀO21 hydrogen bonds, which link the asymmetric unit
into a 3-dimensional network made up of centrosymmetric inter-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.05.
096.
connected R24 (28) rings. There is also a
1 ꢁ y, 1 ꢁ z) contact with a distance of 3.7279 (7) Å [perpendicular
p
furanꢀ ꢀ ꢀ furan (1 ꢁ x,
p
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C. Fernandes et al. / Tetrahedron Letters 57 (2016) 3006–3010
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a
suspension of 50-bromo-20-hidroxyacetophenone