Ionic liquids and ohmic heating in combination for Pd-catalyzed cross-coupling reactions: Sustainable synthesis of flavonoids

Article abstract of DOI:10.3390/molecules25071564

In order to meet the increasing demand for environmentally benign chemical processes, we developed a Suzuki-Miyaura reaction protocol based on the combination of ohmic heating (?H) and supported ionic liquid phase catalysis (SILPC) in aqueous media. This methodology was applied to the synthesis of a series of flavonoid derivatives, including isoflavones, styrylisoflavones, and diarylalkenylisoflavones.

Full text of DOI:10.3390/molecules25071564

molecules
Article
Ionic Liquids and Ohmic Heating in Combination for
Pd-Catalyzed Cross-Coupling Reactions: Sustainable
Synthesis of Flavonoids
Vera L. M. Silva 1 , Raquel G. Soengas 2 and Artur M. S. Silva 1,
*
1
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
verasilva@ua.pt
Department of Organic and Inorganic Chemistry, University of Oviedo, c/Julián Clavería 6,
33006 Oviedo, Spain; rsoengas@uniovi.es
2
*
Correspondence: artur.silva@ua.pt
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Vito Capriati
Received: 24 February 2020; Accepted: 26 March 2020; Published: 29 March 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: In order to meet the increasing demand for environmentally benign chemical processes,
we developed a Suzuki–Miyaura reaction protocol based on the combination of ohmic heating
(ΩH) and supported ionic liquid phase catalysis (SILPC) in aqueous media. This methodology was
applied to the synthesis of a series of flavonoid derivatives, including isoflavones, styrylisoflavones,
and diarylalkenylisoflavones.
Keywords: ionic liquids; ohmic heating; cross-coupling; flavonoids
1. Introduction
Pd-catalyzed cross-coupling reactions exemplify one of the most powerful and popular methods
for the formation of carbon–carbon bonds [1]. The importance of these reactions has driven chemists
to explore alternative procedures. Out of these, some have been truly game-changing, dramatically
accelerating development in the field. One such report appeared in 2000 and described a Suzuki
coupling using the ionic liquid (IL) [bmim][BF4] as reaction media. Inspired by this pioneering
work, several research groups became interested in metal-containing ionic liquids for cross-coupling
reactions. That led to a crucial finding—metal-containing ionic liquids efficiently promote ligand-free
cross-coupling reactions, in which ILs can serve as both immobilization solvent and ligand to the
catalysts [
loss of activity.
For the use in industry, solid catalysis with ILs would be the ideal choice for cross-coupling
2]. The metal-containing IL is highly recyclable and can be used in several cycles without
reactions, avoiding the chance of product contamination by the metal. Thus, the concept of supported
IL phase catalysis (SILPC) for transition metal-catalyzed cross-coupling reactions has gained much
recent attention. Covalently grafting ILs onto the surface of solid materials not only heterogenizes the
expensive IL, but also offers a lot of opportunities to investigate immobilizations of homogeneous metal
complexes or metal nanoparticles [
palladium species present in catalytic systems, ILs are known stabilizing agents for Pd(0) nanoparticles,
observed in most catalytic systems containing palladium precursors without phosphorus ligands [ ].
3]. In addition to acting as co-catalysts able to modify the activity of
4
The solid-supported IL would immobilize and stabilize the formed Pd(0) nanoparticles, which can
be then recovered from the catalytic mixture and reused with almost unchanged activity. A further
advantage of basing Pd-catalyzed cross-coupling reactions in SILPC is that such reactions are usually
performed in water and are significantly enhanced by microwave (MW) heating. However, MW
heating has some important limitations that remain unsolved. One important drawback is related
Molecules 2020, 25, 1564; doi:10.3390/molecules25071564
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to the low efficiency of the magnetron in converting electrical energy into microwave energy (about
50–60%) [ ]. Thus, in the case of reflux using an open vessel system on a small scale, microwave
5
radiation consumes significantly more energy than conventional heating (mantle or oil bath). In
addition, scaling-up reactions under MW heating is problematic due to the limited penetration depth of
microwave radiation in absorbing media. This fact, together with safety concerns, makes MW heating
not suitable for its application to industrial scale [6].
In order to overcome these limitations, we have developed in our group an alternative based
on the use of ohmic heating (ΩH) for chemical reactions [7,8]. In this thermal process the reaction
mixture, which serves as an electrical resistor, is heated by passing electricity through it (electrodes
are in contact with the conductive reaction medium). Thermal energy is generated by the motion
of the charged species in solution as a result of the high frequency (25 kHz) AC electric current.
The thermal-energy transfer occurs mostly between the electrode plates cross-session region and
surroundings. Electrical energy is dissipated into heat with high efficiency, providing a high-speed
heating rate, rapid, and uniform heating (temperature homogeneity), as well as an enhancement
of the charged-species dynamics, which can conduct to a distinct reactivity path.
same effects as MW activation on the reaction, reducing the reaction time and also activating metal
surface and facilitating single electron transfer (SET) reactions [ ]. Our ohmic-reactor operates at
ΩH leads to the
9
atmospheric pressure, under open-vessel conditions, and typically at the boiling temperature of the
solvent (Figure 1) [10].
Figure 1. Schematic representation of the ohmic heating reactor.
Given that
electrically conductive, water in combination with SILPC is a propitious solvent for this process. On the
other hand, the combination of H and water as solvent provides great opportunities for sustainable
ΩH is ideally suitable for synthesis in aqueous media, in which the reaction mixture is
Ω
chemistry. Water is non-toxic, non-flammable, and is easily available at low cost. In addition, water has
a high thermal capacity, making the exothermic processes safer and more selective, especially when
they are performed on a large scale. Moreover, ohmic heating is already used in industry, especially
for food processing, with several major equipment manufacturers offering commercial ohmic heaters,
serving a growing market of food manufacturing companies, so the combination of
ΩH and SILPC
in aqueous media may be of interest not only from the perspective of green chemistry but also of
industrial scalability.
In order to demonstrate the usefulness of this strategy, we envisioned its application to the
synthesis of the biologically relevant class of compounds such as flavonoids.
Flavonoids are a family of natural products present as secondary metabolites in plants,
which display remarkable biological activity including antimalarial, anticancer, antioxidant, and
anti-inflammatory activities [11–20]. Due to their biological profile, numerous approaches have been

Molecules 2020, 25, 1564
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reported for the synthesis of flavonoid derivatives. Among them, palladium-catalyzed cross-coupling
reactions are gaining much recent interest [21 27], the Suzuki–Miyaura coupling reaction being the most
frequently used methodology [28]. In this regard, H-enhanced cross-coupling reactions, and especially
–
Ω
Suzuki–Miyaura reactions, have proven particularly useful for the synthesis of pharmacologically
relevant scaffolds [29,30].
Herein we describe the combination of
ΩH and SILPC for the Suzuki cross-coupling reaction and
its application to the synthesis and functionalization of flavonoids.
2. Results and Discussion
We started our studies with the immobilization of the Pd catalyst. For this purpose, we used
the immobilization procedure described by Hagiwara et al., in which Pd(OAc)2 was supported on
amorphous silica with the aid of an imidazolium ionic liquid ([bmim]PF6) [31,32]. The procedure of
immobilization is quite simple; a suspension of spherical amorphous silica in a solution of Pd(OAc)2 in
[bmim]PF6 and CH2Cl2 was evaporated to dryness and washed with diethyl ether, to afford a powdery
and free-flowing immobilized catalyst (Pd@SILP). Structural studies suggest that the catalyst consists
of a solution of Pd(OAc)2 in [bmim]PF6 physisorbed in the SiO2 pores [31].
Initially, the Suzuki–Miyaura reaction under the supported Pd catalyst was assessed with the
coupling of 3-bromochromone 1a and phenylboronic acid 2a under various conditions, and the results
are compiled in Table 1. Water was identified as the optimal solvent; combined with TBAB as PTC
(phase transfer catalyst) furnished the desired isoflavone 3a in 89% yield via conventional heating at
100 ◦C for 12 h (Table 1, entry 6). With the optimized conditions in hand, we investigated the effect of
the use of ohmic heating on the yield and the reaction rate. Thus, when 0.5 mmol of 1a was allowed to
react with 0.6 mmol of phenylboronic acid 2a in the presence of 0.5 mmol of Na2CO3 as a base, 0.1 mol%
of TBAB (tetrabutylammonium bromide) as PTC (phase transfer catalyst) and 1 mol% of Pd-supported
catalyst in water at 100 ◦C under ohmic heating, the reaction proceeded in 1 h and afforded isoflavone
3a in an excellent 93% yield (Table 1, entry 7). Decreasing the catalyst loading to 0.1 mol% did not
significantly affect the yield (Table 1, entry 8). The catalyst loading can be further decreased to 0.05
mol%; under such conditions, isoflavone 3a was formed in a 90% yield (Table 1, entry 9).
Table 1. Suzuki–Miyaura reaction of 3-bromochromone 1a and phenylboronic acid 2a.
Entry
Solvent
mol% Pd
TBAB (mol%)
T (◦C)
Time (h)
Yield (%) a
100 b
100 b
100 b
1
2
3
bmim[Br]
bmim[PF6]
DMF
1
1
1
-
-
-
12
12
12
34
65
69
DMF/H2O
5:2
100 b
4
1
-
12
72
100 b
100 b
100 c
100 c
100 c
5
6
7
8
9
H2O
H2O
H2O
H2O
1
1
1
0.1
0.05
a
-
12
12
1
1
1
9
0.1
0.1
0.1
0.1
89
93
92
90
H2O
isolated yield; b oil bath; c ohmic heating.
The work-up procedure is very simple: the reaction mixture was filtered, washing thoroughly
with water. After extraction with diethyl ether, 1H NMR of the crude reaction product indicated that
1a was fully transformed to the isoflavone 3a.

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The application of the optimized protocol to a range of flavonoid bromides is described in Table 2.
In a typical procedure, a mixture of flavonoid bromide
in water was heated under ohmic heating at 100 C in the presence of TBAB (0.1 mol%), Na2CO3
(0.5 mmol) and Pd@SILPC (0.05 mol%) for 1 h.
1 (0.5 mmol) and aryl boronic acid 2 (0.6 mmol)
◦
Table 2. Suzuki–Miyaura reactions of bromoflavones 1 with arylboronic acids 2.
Yield
Entry
R1
R2
R3
1
R4
2
Product
3
(%)a
1
Br
H
H
1a
Ph
2a
3a
93
2
3
4
5
Br
Br
H
H
H
H
1a
1a
1b
1b
3,4-OMeC6H3
4-ClC6H4
Ph
2b
2c
2a
2b
3b
3c
3d
3e
89
91
90
85
H
H
H
3,4-OMeC6H3
6
7
H
H
OBn
H
1c
3,4-OMeC6H3
3,4-OMeC6H3
2b
2b
3f
81
82
1d
3g
8
9
Cl
H
H
OBn
H
1e
1f
4-ClC6H4
4-ClC6H4
2c
2c
2b
3h
3i
3j
89
85
80
10
Me
1g
3,4-OMeC6H3
a
Isolated yield.
Coupling of 1 proceeded smoothly regardless of the electronic nature of the substituents. Thus,
the coupling reaction of 1a and both electron-deficient and electron-rich arylboronic acids afforded in
all cases the corresponding isoflavones 3a in high yield (Table 2, entries 1–3). Bromovinyl chromones
1b also underwent the coupling reaction with boronic acids 2a affording 3-styrylchromones 3d in
good yields (Table 2, entries 4–6). Interestingly, the coupling of 2.0 equiv. of arylboronic acids 2b with
gem-dibromovinyl bromoflavones 1d afforded the corresponding bisarylvinyl chromones 3g in
–
c
,
c
,b
–f
,
c
–
g
–j
good yields. To the best of our knowledge, the biological profile of this family of chromone derivatives
remains unexplored, which is surely related to the lack of an efficient procedure for the synthesis of
these flavonoid derivatives. In fact, there is just one example in the literature in which bisarylvinyl
chromones are obtained in low yields by the reaction of formyl chromone and ketene. [33]
The lifetime of the catalyst and its level of reusability are very important factors for practical
applications. In order to evaluate this issue, we envisioned a series of experiments using the recycled
catalyst. Thus, we performed the reaction of 3-bromochromone 1a with phenylboronic acid 2a on

Molecules 2020, 25, 1564
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a 5 mmol scale. After the completion of the first reaction to afford the corresponding isoflavone 3a
in 93% yield, the catalyst was recovered by filtration, washing the reaction vessel and electrodes
thoroughly with distilled water and n-pentane. After drying the recovered catalyst in vacuum at 40 ◦C
for 5 h, a new reaction was performed with fresh solvent and reactants under the same conditions.
Gratifyingly, the supported Pd@SILP system could be reused three times with no considerable loss of
activity, affording isoflavone 3a with an average chemical yield of 88.3%. In addition, isoflavone 3a
was analyzed through ICP-MS, showing negligible Pd contamination (3.48 ppb).
3. Materials and Methods
NMR spectra were recorded on a 300 MHz NMR spectrometer [300.13 MHz (1H), 75.47 MHz
(13C)] with TMS as an internal reference and with CDCl3 as a solvent. Chemical shifts (δ) are quoted in
ppm relative to TMS. Coupling constants (J) are quoted in Hz. Mass spectra analysis (ESI-MS) and
high-resolution mass spectra analysis (ESI-HRMS, 70 eV) were carried out on an electrospray ionization
mass spectrometer with a micro-TOF (time-of-flight) analyzer. For experiments carried out under
ohmic heating, the 10 mL reactor was filled with the reaction mixture closed, and the mixture was
heated to 100 ◦C. For 4 mL of reaction mixture the length of electrodes immersed in the reaction medium
was 9 mm; the distance between the electrodes was 10 mm. Medium magnetic stirring speed (740 rpm)
was used in all the experiments carried out in the ohmic heating reactor. Temperature measurement
was done using a type J glass-sheathed thermocouple inside the reactor. For the experiments carried
out in conventional heating (oil bath), medium magnetic stirring speed (740 rpm) was used.
3.1. Representative Procedure for Catalyst Preparation
To a stirred solution of Pd(OAc)2 (12 mg) in [bmim]PF6 (0.1 g) and CH2Cl2 (10 mL) was added
silica powder (1 g, spherical for flash column chromatography, diameter; 40–50 mm, pore size; 5–7 nm,
pore volume; 0.80–1.00 mL/g, surface area; 600–700 m2/g). After being stirred for 90 min at room
temperature, CH2Cl2 was evaporated to dryness to give a light brown dry powder, which was rinsed
with diethyl ether and dried in vacuo to afford the Pd supported catalyst (~1% wt based on weight gain).
3.2. General Procedure for the Suzuki–Miyaura Reaction.
A mixture of the corresponding bromochromone
1 (0.50 mmol), the corresponding boronic acid 2
(0.60 mmol), Na2CO3 (0.50 mmol) and Pd@SILP (0.05% mmol of Pd) in H2O was stirred under ohmic
◦
heating at 100 C for 1 h. The catalyst was filtered-off and the filtrate was extracted with Et2O (3
×
10 mL). The combined extracts were dried over Na2SO4 and evaporated under reduced pressure
affording products . The physical data of known isoflavones 3a were comparable to those of the
3
–f
literature [34–38]. The physical data of the new isoflavones 3g–j are shown below.
3-[2,2-Bis(3,4-dimethoxyphenyl)vinyl]-4H-chromen-4-one (3g): 1H NMR (300 MHz, CDCl3)
δ 8.27
(ddd, J = 8.0, 1.7, 0.5 Hz, 1H), 7.63 (ddd, J = 8.7, 7.2, 1.7 Hz, 1H), 7.50–7.30 (m, 3H), 6.99 (d, J = 1.0 Hz,
1H), 6.96 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.84–6.76 (m, 3H), 6.74 (d, J = 1.8 Hz, 1H), 3.92 (s,
3H), 3.89 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 176.6, 156.2, 152.8, 149.1, 148.8,
142.9, 133.6, 126.4, 125.3, 125.1, 124.5, 124.5, 121.1, 118.1, 112.4, 112.3, 111.2, 56.0, 56.0. HRMS (ESI+) [M
+ H]+ calculated for C25H20O6, 445.1646; found, 445.1649.
1
3-[2,2-Bis(4-chlorophenyl)vinyl]-6-chloro-4H-chromen-4-one (3h): H NMR (300 MHz, CDCl3)
δ
8.22
(dd, J = 2.6, 0.4 Hz, 1H), 7.59 (dd, J = 8.9, 2.6 Hz, 1H), 7.42–7.27 (m, 5H), 7.23 (s, 1H), 7.21–7.11 (m, 4H),
6.99 (d, J = 1.1 Hz, 1H).13C NMR (75 MHz, CDCl3)
δ 175.9, 155.0, 154.8, 142.5, 140.1, 137.8, 134.2, 134.0,
133.9, 131.3, 131.3, 129.5, 128.9, 128.5, 125.5, 124.6, 121.7, 119.9, 117.8. HRMS (ESI+) [M + H]+ calculated
for C23H14Cl3O6, 427.0054; found, 427.0042.
7-(Benzyloxy)-3-[2,2-bis(4-chlorophenyl)vinyl]-4H-chromen-4-one (3i): 1H NMR (300 MHz, CDCl3)
δ
8.17 (d, J = 8.9 Hz, 1H), 7.47–7.31 (m, 8H), 7.31-7.26 (m, 2H), 7.24–7.13 (m, 4H), 7.05 (dd, J = 8.9,

Molecules 2020, 25, 1564
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2.4 Hz, 1H), 7.02 (d, J = 1.2 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 5.13 (s, 2H). 13C NMR (75 MHz, CDCl3)
δ
177.4, 155.8, 154.8, 149.5, 149.2, 148.7, 148.6, 143.7, 135.4, 133.6, 132.6, 126.2, 125.2, 123.8, 122.4, 122.2,
120.8, 118.2, 115.3, 112.8, 111.6, 110.7, 110.6, 56.0. HRMS (ESI+) [M + H]+ calculated for C30H21Cl2O3,
499.0862; found, 499.0860.
3-[2,2-Bis(3,4-dimethoxyphenyl)vinyl]-6-methyl-4H-chromen-4-one (3j): 1H NMR (300 MHz, CDCl3)
δ
8.04 (dd, J = 2.2, 1.0 Hz, 1H), 7.43 (dd, J = 8.6, 2.2 Hz, 1H), 7.36 (d, J = 1.0 Hz, 1H), 7.23 (s, 1H), 7.19 (t,
J = 2.4 Hz, 1H), 7.04–6.97 (m, 2H), 6.92-6.85 (m, 2H), 6.83–6.79 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.84 (s,
3H), 3.74 (s, 3H), 2.45 (s, 3H). 13C NMR (75 MHz, CDCl3)
177.4, 154.7, 154.0, 149.3, 149.0, 148.6, 148.4,
δ
143.4, 135.3, 135.1, 130.7, 130.4, 125.3, 125.1, 123.3, 122.4, 120.7, 117.8, 115.4, 112.8, 111.4, 110.6, 110.5,
56.0, 55.9, 55.8, 21.0. HRMS (ESI+) [M + H]+ calculated for C26H23O4, 399.1591; found, 399.1598.
4. Conclusions
In summary, we have developed an environmentally benign, economically friendly, and sustainable
Suzuki–Miyaura reaction of bromochromones and boronic acids employing Pd(II) immobilized in a
silica-supported ionic liquid in water using ohmic heating.
This method offers significant improvements over existing procedures, as the absence of undesired
side reactions, the short reaction times, the mild conditions required, the wide range of functionalities
tolerated, the good yields, the environment-friendly reaction conditions, and the low catalyst loading. In
addition, the supported catalyst can be recovered and maintains a good activity for at least three cycles.
Thus, the combination of ohmic heating with supported ionic liquid phase catalysis (SILPC) in
water not only is of considerable interest for cross-coupling reactions but also provides a convenient
alternative to the existing methodologies for the synthesis of flavonoid derivatives, including isoflavones,
3-stryrylchromones, and the elusive 3-diarylvinylchromones.
Author Contributions: V.L.M.S., R.G.S. and A.M.S.S. conceived and designed the research. V.L.M.S. and R.G.S.
performed the experiments. A.M.S.S. guided the experiments and supervised the data. V.L.M.S., R.G.S. and
A.M.S.S. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: Thanks are due to University of Aveiro and FCT for the financial support to the QOPNA research unit
(FCT UID/QUI/00062/2019) through national founds and where applicable co-financed by the FEDER, within the
PT2020 Partnership Agreement, and also to the Portuguese NMR Network. Vera L. M. Silva also thanks for the
Assistant Professor position within CEE-CINST/2018; since 01/09/2019.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Seechurn, C.C.C.J.M.; Kitching, O.; Colacot, T.J.; Snieckus, V. Palladium-catalyzed cross-coupling: a historical
contextual perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed. 2012, 51, 5062–5085. [CrossRef]
Sasaki, T.; Zhong, C.; Tada, M.; Iwasawa, Y. Immobilized metal ion-containing ionic liquids: Preparation,
structure and catalytic performance in Kharasch addition reaction. Chem. Commun. 2005, 2506–2608.
[CrossRef]
2.
3.
4.
5.
6.
7.
Riisager, A.; Fehrmann, R. Imidazolium-based ionic liquids grafted on solid surfaces. Chem. Soc. Rev. 2014
43, 7171–7187. [CrossRef]
Migowski, P.; Dupont, J. Catalytic applications of metal nanoparticles in imidazolium ionic liquids. Chem.:
Eur. J. 2007, 13, 32–39. [CrossRef]
Razzaq, T.; Kappe, C.O. On the energy efficiency of microwave-assisted organic reactions. Chem. Sus. Chem.
2008, 1, 123–132. [CrossRef]
Nuchter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Microwave assisted synthesis–a critical technology
overview. Green Chem. 2004, 6, 128–141. [CrossRef]
,
Pinto, J.; Silva, V.L.M.; Silva, A.M.G.; Silva, A.M.S.; Costa, J.C.S.; Santos, L.M.N.B.F.; Enes, R.; Cavaleiro, J.A.S.;
Vicente, A.A.M.O.S.; Teixeira, J.A.C. Ohmic heating as a new efficient process for organic synthesis in water.
Green Chem. 2013, 15, 970–975. [CrossRef]

Molecules 2020, 25, 1564
7 of 8
8.
9.
Silva, V.L.M.; Santos, L.M.N.B.F.; Silva, A.M.S. Ohmic heating: An emerging concept in organic synthesis.
Chem. Eur. J. 2017, 23, 7853–7865. [CrossRef] [PubMed]
Soengas, R.G.; Silva, V.L.M.; Pinto, J.; Rodríguez-Solla, H.; Silva, A.M.S. Ohmic heating and ionic liquids in
combination for the indium-promoted synthesis of 1-halo alkenyl compounds: applications to Pd-catalysed
cross-coupling reactions. Eur. J. Org. Chem. 2016, 99–107. [CrossRef]
10. Silva, V.L.M.; Silva, A.M.S.; Santos, L.M.N.B.F.; Silva, A.M.G.; Pinto, J.; Enes, R.; Cavaleiro, J.A.S.;
Vicente, A.A.M.O.S.; Teixeira, J.A.C.; Morais, A.; et al. Reator para síntese química com aquecimento
óhmico, método e suas aplicações, PT105908, 27-09-2011.
11. Imran, M.; Rauf, A.; Abu-Izneid, T.; Nadeem, M.; Shariati, M.A.; Khan, I.A.; Imran, A.; Orhan, I.E.; Rizwan, M.;
Atif, M.; et al. Luteolin, a flavonoid, as an anticancer agent: A review. Biomed. Pharmacother. 2019, 112,
108612–108622. [CrossRef]
12. Mirossay, L.; Varinská, L.; Mojžiš, J. Antiangiogenic effect of flavonoids and chalcones: an update. Int. J. Mol.
Sci. 2018, 19, 27. [CrossRef]
13. Proença, C.; Freitas, M.; Ribeiro, D.; Tomé, S.M.; Oliveira, E.F.T.; Viegas, M.F.; Araújo, A.N.; Ramos, M.J.;
Silva, A.M.S.; Fernandes, P.A.; et al. Evaluation of a flavonoids library for inhibition of pancreatic α-amylase
towards a structure-activity relationship. J. Enz. Inhib. Med. Chem. 2019, 34, 577–588. [CrossRef]
14. Proença, C.; Freitas, M.; Ribeiro, D.; Oliveira, E.F.T.; Sousa, J.L.C.; Tomé, S.M.; Ramos, M.J.; Silva, A.M.S.;
Fernandes, P.A.; Fernandes, E. -Glucosidase inhibition by flavonoids: An in vitro and in silico
α
structure-activity relationship study. J. Enz. Inhib. Med. Chem. 2017, 32, 1216–1228. [CrossRef] [PubMed]
15. Matos, A.M.; Man, T.; Idrissi, I.; Souza, C.C.; Mead, E.; Dunbar, C.; Wolak, J.; Oliveira, M.C.; Evans, D.;
Grayson, J.; et al. Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic
potential against Alzheimer’s disease: Synthesis, binding affinity towards amyloid
ability to disrupt Aβo-PrPC interactions. Pure Appl. Chem. 2019, 91, 1107–1136. [CrossRef]
16. Ribeiro, D.; Freitas, M.; Tom , S.M.; Silva, A.M.S.; Laufer, S.; Lima, J.L.F.C.; Fernandes, E. Flavonoids inhibit
β oligomers (Aβo) and
é
COX-1 and COX-2 enzymes and cytokine/chemokine production in human whole blood. Inflammation 2015
38, 858–870. [CrossRef]
,
17. Freitas, M.; Ribeiro, D.; Tomé, S.M.; Silva, A.M.S.; Fernandes, E. Synthesis of chlorinated flavonoids with
anti-inflammatory and pro-apoptotic activities in human neutrophils. Eur. J. Med. Chem. 2014, 86, 153–164.
[CrossRef]
18. Ribeiro, D.; Freitas, M.; Tomé, S.M.; Silva, A.M.S.; Porto, G.; Fernandes, E. Modulation of human neutrophils’
oxidative burst by flavonoids. Eur. J. Med. Chem. 2013, 67, 280–292. [CrossRef]
19. Gomes, A.; Neuwirth, O.; Freitas, M.; Couto, D.; Ribeiro, D.; Figueiredo, A.G.P.R.; Silva, A.M.S.;
Seixas, R.S.G.R.; Pinto, D.C.G.A.; Tomé, A.C.; et al. Synthesis and antioxidant properties of new chromone
derivatives. Bioorg. Med. Chem. 2009, 17, 7218–7226. [CrossRef]
20. Silva, C.F.M.; Pinto, D.C.G.A.; Silva, A.M.S. Chromones: A promising ring system for new anti-inflammatory
drugs. Chem. Med. Chem. 2016, 11, 2252–2260. [CrossRef]
21. Springsteel, M.F.; Galietta, L.J.V.; Ma, T.; By, K.; Berger, G.O.; Yang, H.; Dicus, C.W.; Choung, W.; Quan, C.;
Shelat, A.A. Benzoflavone activators of the cystic fibrosis transmembrane conductance regulator: Towards
a pharmacophore model for the nucleotide-binding domain. Bioorg. Med. Chem. 2003, 11, 4113–4120.
[CrossRef]
22. Ko, S.K.; Jang, H.J.; Kim, E.; Park, S.B. Concise and diversity-oriented synthesis of novel scaffolds embedded
with privileged benzopyran motif. Chem. Commun. 2006, 2962–2964. [CrossRef] [PubMed]
23. Dao, T.T.; Kim, S.B.; Sin, K.S.; Kim, S.; Kim, H.P.; Park, H. Synthesis and PGE2 inhibitory activity of vinylated
and allylated chrysin analogues. Arch. Pharmacol Res. 2003, 26, 581–584. [CrossRef] [PubMed]
24. Pal, M.; Parasuraman, K.; Subramanian, V.; Dakarapu, R.; Yeleswarapu, K.R. Palladium mediated
stereospecific synthesis of 3-enynyl substituted thioflavones/flavones. Tetrahedron Lett. 2004, 45, 2305–2309.
[CrossRef]
25. Pal, M.; Dakarapu, R.; Parasuraman, K.; Subramanian, V.; Yeleswarapu, K.R. Synthesis of isocoumarins via
Pd/C-mediated reactions of o-iodobenzoic acid with terminal alkynes. J. Org. Chem. 2005, 70, 7179–7187.
[CrossRef] [PubMed]
26. Joo, Y.H.; Kim, J.K.; Kang, S.H.; Noh, M.S.; Ha, J.Y.; Choi, J.K.; Lim, K.M.; Lee, C.H.; Chung, S.
2,3-Diarylbenzopyran derivatives as a novel class of selective cyclooxygenase-2 inhibitors. Bioorg. Med.
Chem. Lett. 2003, 13, 413–417. [CrossRef]

Molecules 2020, 25, 1564
8 of 8
27. Fitzmaurice, R.J.; Etheridge, Z.C.; Jumel, E.; Woolfson, D.N.; Caddick, S. Microwave enhanced palladium
catalysed coupling reactions: A diversity-oriented synthesis approach to functionalized flavones. Chem.
Commun. 2006, 4814–4816. [CrossRef]
28. Selepe, M.A.; Van Heerden, F.R. Application of the Suzuki-Miyaura reaction in the synthesis of flavonoids.
Molecules 2013, 18, 4739–4765. [CrossRef]
29. Pinto, J.; Silva, V.L.M.; Silva, A.M.G.; Santos, L.M.N.B.F.; Silva, A.M.S. Ohmic heating-assisted Synthesis of
3-Arylquinolin-4(1H) ones by a Reusable and ligand-free Suzuki-Miyaura reaction in water. J. Org. Chem.
2015, 80, 6649–6659. [CrossRef]
30. Pinto, J.; Silva, V.L.M.; Santos, L.M.N.B.F.; Silva, A.M.S. Synthesis of (E)-3-Styrylquinolin-4(1H)-ones in water
by ohmic heating: A comparison with other methodologies. Eur. J. Org. Chem. 2016, 2888–2896. [CrossRef]
31. Hagiwara, H.; Sugawara, Y.; Isobe, K.; Hoshi, T.; Suzuki, T. Immobilization of Pd(OAc)2 in ionic liquid on
silica: Application to sustainable Mizoroki-Heck reaction. Org. Lett. 2004, 6, 2325–2328. [CrossRef]
32. Soengas, R.; Navarro, Y.; Iglesias, M.J.; López-Ortiz, F. Immobilized gold nanoparticles prepared from
Gold(III)-containing ionic liquids on silica: application to the sustainable synthesis of propargylamines.
Molecules 2018, 23, 2975. [CrossRef] [PubMed]
33. Eiden, F.; Schünemann, J. Reaction of Formylchromones with Dichloroketene. Arch. Pharm. 1984, 317,
970–972. [CrossRef]
34. Felpin, F.-X. Practical and efficient Suzuki Miyaura cross-coupling of 2-iodocycloenones with arylboronic
−
acids catalyzed by recyclable Pd(0)/C. J. Org. Chem. 2005, 70, 8575–8578. [CrossRef] [PubMed]
35. Vasselin, D.A.; Westwell, A.D.; Matthews, C.S.; Bradshaw, T.D.; Stevens, M.F.G. Structural studies on
bioactive compounds. 40.1 Synthesis and biological properties of fluoro-, methoxyl-, and amino-substituted
3-phenyl-4H-1-benzopyran-4-ones and a comparison of their antitumor activities with the activities of related
2-phenylbenzothiazoles. J. Med. Chem. 2006, 49, 3973–3981. [CrossRef] [PubMed]
36. Armelin, E.A.; Donate, P.M.; Galembeck, S.E. Effect of the environment on the reactivity of 4’-substituted
flavones and isoflavones. Tetrahedron 2000, 56, 5105–5111. [CrossRef]
37. Davies, S.G.; Mobbs, B.E.; Goodwin, C.J. Substituted 4H-1-benzopyran-4-ones (chromones): Synthesis via
palladium-catalysed coupling of their halogeno derivatives with alkenes. J. Chem. Soc. Perkin Trans. 1 1987
2597–2604. [CrossRef]
,
38. Takao, K.; Ishikawa, R.; Sugita, Y. Synthesis and biological evaluation of 3-styrylchromone derivatives as free
radical scavengers and α-glucosidase inhibitors. Chem. Pharm. Bull. 2014, 62, 810–815. [CrossRef]
Sample Availability: Samples of the compounds 3a-e are available from the authors.
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