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Chromones as versatile building blocks in cycloaddition reactions
Publication . Albuquerque, Hélio; Santos, Clementina M.M.; Cavaleiro, João; Silva, Artur
4H-Chromen-4-ones commonly referred as chromones are a class of naturally occurring
heterocyclic compounds implicated in a series of biological and pharmacological properties.[1] It is
also an interesting scaffold involved in a range of chemical transformations for the preparation of
novel and more complex oxygen-containing heterocyclic derivatives.[2]
Following our interest in the chemistry of chromones, we design two different building blocks, 2-
[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones 1 and (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4Hchromen-
4-ones 2, and explore the reactivity of the unsaturated systems in cycloaddition reactions.
In the former case, chromones 1 were used as dienes in microwave-assisted Diels–Alder (DA)
reactions with various electron-poor and electron-rich dienophiles to provide flavone-type
compounds 3.[3] In the latter case, the diene system of chromones 2 was involved in DA reactions
with N-methylmaleimide whereas the acetylene moiety react with sodium azide, via 1,3-dipolar
cycloaddition reaction, to afford xanthene-1,2,3-triazole dyads 4.[4] In this communication, we will
present and discuss the synthetic details and spectroscopic characterization of the main products and
some interesting byproducts, as well as the intermediate compounds isolated in each case.
Conjugate additions of carbon nucleophiles to chromone derivatives towards nitrogen heterocycles
Publication . Albuquerque, Hélio; Santos, Clementina M.M.; Cavaleiro, José; Silva, Artur
Conjugate additions of
nitromethane to the extended π-
system of chromone derivatives
afforded the 1,6-conjugate
addition products, together with
structure complex oxygen
heterocycles through tandem
processes. Further
functionalization of targeted
adducts allowed the preparation
of biological relevant nitrogen
heterocycles such as
styrylpyrrolidines, as well as
pyrazole and bis-pyrazole
derivatives.
Novel chromone and xanthone derivatives: synthesis and ROS/RNS scavenging activities
Publication . Proença, Carina; Albuquerque, Hélio; Ribeiro, Daniela; Freitas, Marisa; Santos, Clementina M.M.; Silva, Artur; Fernandes, Eduarda
Chromones and xanthones are oxygen-containing heterocyclic compounds acknowledged by their antioxidant properties. In an effort to develop novel agents with improved activity, a series of compounds belonging to these chemical classes were prepared. Their syntheses involve the condensation of appropriate 2-methyl-4H-chromen-4-ones, obtained via Baker-Venkataraman rearrangement, with (E)-3-(3,4-dimethoxyphenyl)acrylaldehyde to provide the corresponding 2-[(1E,3E)-4-(3,4-dimethoxyphenyl)buta-1,3-dien-1-yl]-4H-chromen-4-ones. Subsequent electrocyclization and oxidation of these compounds led to the synthesis of 1-aryl-9H-xanthen-9-ones. After cleavage of the protecting groups, hydroxylated chromones and xanthones were assessed as scavenging agents against both reactive oxygen species (ROS) [superoxide radical (O2(•-)), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen ((1)O2), and peroxyl radical (ROO(•))] and reactive nitrogen species (RNS) [nitric oxide ((•)NO) and peroxynitrite anion (ONOO(-))]. Generally, all the tested new hydroxylated chromones and xanthones exhibited scavenger effects dependent on the concentration, with IC50 values found in the micromolar range. Some of them were shown to have improved scavenging activity when compared with previously reported analogues, allowing the inference of preliminary conclusions on the structure-activity relationship.
2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in Diels–Alder reactions: experimental and computational studies
Publication . Albuquerque, Hélio; Santos, Clementina M.M.; Lima, Carlos F.R.A.C.; Santos, Luís M.N.B.F.; Cavaleiro, José; Silva, Artur
The synthesis and reactivity of 2-[(1 £,3£)-4-arylbuta-1 ,3-dien-l-yl]-4H-chromen-4-ones 1 as
dienes in Diets-Alder (DA) reactions towards several electron-poor and electron-rich
dienophiles under microwave irradiation was studied. The optimized reaction conditions were
achieved by using N-methylmaleimide2 as dienophile and Sc(0Tf)3 as Lewis acid under
microwave-assisted and solvent-free conditions. The Lewis acid improved the reaction yields
since it prevented the adducts obtained to undergo a second DA reaction, thus avoiding
formation of a bisadduct. The a,~:y ,o-diene of the starting chromones showed to be the most
reactive and the computational results confirmed the experimental findings. Theoretical
calculations also allowed explaining some unexpected lack of reactivity by some dienophiles.
The adducts prepared were dehydrogenated by using DDQ, however, the aza-adducts showed
to be sensitive to the high energetic reaction conditions necessary to perform the
aromatization.
Synthesis of xanthone-1,2,3-triazole dyads
Publication . Albuquerque, Hélio; Santos, Clementina M.M.; Silva, Artur; Cavaleiro, José
Xanthones and 1,2,3-triazoles are known to exhibit several biological, pharmacological and biocidal
properties[1]. The potential applications of these two classes of heterocycles led us to develop new
strategies to synthesize xanthone-1,2,3-triazole dyads, aiming to get potentially improved therapeutic
agents[2]. With this rational in mind we designed and synthesized novel chromone derivatives 1a-d to be
used as building motifs and to explore the reactivity of the two unsaturated systems (the diene and the
alkyne). In the present communication we will present a new synthetic route towards the synthesis of
xanthone-1,2,3-triazole dyads 7a-d using consecutively the azide-alkyne Huisgen 1,3-dipolar
cycloaddition and Diels-Alder reaction. Our approach involves the synthesis chromone-triazole
derivatives 2a-d using the reaction of 1a-d with sodium azide, followed by the methylation of the NH of
the triazole moiety. The methylation afforded three isomers 3a-d, 4a-d and 5a-d, as expected. The major
isomers 3a-d were used in the Diels-Alder reaction with N-methylmaleimide, and the adducts obtained
6a-d were oxidized to afford the xanthone-1,2,3-triazole dyads 7a-d. All the synthetic details as well as
the structural characterization (by 1D and 2D NMR studies) of the new synthesised compounds will be
presented and discussed.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
SFRH
Funding Award Number
SFRH/BD/86277/2012