Synthesis of (E)-2-styrylchromones and flavones by base-catalyzed cyclodehydration of the appropriate β-diketones using water as solvent

Article abstract of DOI:10.3390/molecules200611418

A low cost, safe, clean and environmentally benign base-catalyzed cyclodehydration of appropriate β-diketones affording (E)-2-styrylchromones and flavones in good yields is disclosed. Water was used as solvent and the reactions were heated using classical

Full text of DOI:10.3390/molecules200611418

Molecules 2015, 20, 11418-11431; doi:10.3390/molecules200611418
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of (E)-2-Styrylchromones and Flavones by
Base-Catalyzed Cyclodehydration of the Appropriate
β-Diketones Using Water as Solvent
Joana Pinto 1, Vera L. M. Silva 1,*, Ana M. G. Silva 2 and Artur M. S. Silva 1,*
1
Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal;
E-Mail: jfpinto@ua.pt
2
UCIBIO/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, 4169-007 Porto, Portugal; E-Mail: ana.silva@fc.up.pt
* Authors to whom correspondence should be addressed;
E-Mails: verasilva@ua.pt (V.L.M.S.); artur.silva@ua.pt (A.M.S.S.);
Tel.: +351-234-370-714 (A.M.S.S.); Fax: +351-234-370-084 (A.M.S.S.).
Academic Editor: Kei Saito
Received: 30 April 2015 / Accepted: 16 June 2015 / Published: 22 June 2015
Abstract: A low cost, safe, clean and environmentally benign base-catalyzed cyclodehydration
of appropriate β-diketones affording (E)-2-styrylchromones and flavones in good yields is
disclosed. Water was used as solvent and the reactions were heated using classical and
microwave heating methods, under open and closed vessel conditions. β-Diketones having
electron-donating and withdrawing substituents were used to evaluate the reaction scope.
The reaction products were isolated in high purity by simple filtration and recrystallization
from ethanol, when using 800 mg of the starting diketone under classical reflux
heating conditions.
Keywords: (E)-2-styrylchromones; flavones; cyclodehydration reactions; microwave heating;
reactions in water
1. Introduction
Flavones (I), the most prominent group of naturally occurring chromones, are present in a wide
variety of plants [1] and are well-known by their broad range of biological properties, such as

Molecules 2015, 20
11419
antibacterial, antifungal [2,3], antiviral [4], antiinflammatory [5], antioxidant [6], antiallergic [7],
hepatoprotective [8], antithrombotic and antitumoral [9,10] activities (Figure 1). In contrast to flavones,
there are only nine natural (E)-2-styrylchromones II–X [11–15], a group of oxygen heterocyclic
compounds that although being scarce in Nature have shown significant biological activities [16–18]
(Figure 1). 2-Styrylchromones have potential therapeutic applications in the treatment of cancer [19],
allergies [20], viral infections [21], gout [22] and oxidative stress related damage [23]. These compounds
have demonstrated strong protective effects against pro-oxidant agents observed in cellular [23] and in
non-cellular systems [24], making them good antioxidant compound candidates.
Figure 1. Structures of flavone I and naturally occurring (E)-2-styrylchromones II–X.
The most common strategies for the synthesis of (E)-2-styrylchromones are the aldol condensation
of 2′-hydroxyacetophenone derivatives with cinnamaldehydes, followed by cyclodehydrogenation of
the formed 2′-hydroxycinnamylideneacetophenones, and the Baker-Venkataraman method [16–18,25].
This second strategy involves the O-acylation of 2′-hydroxyacetophenone (1, Scheme 1, step i)
followed by base-catalyzed rearrangement of the formed esters 3 to give 5-aryl-1-(2-hydroxyphenyl)pent-
4-ene-1,3-diones 4 (which exist in equilibrium with their enolic form; Scheme 1, step ii). This
rearrangement can be performed in high yield under solvent-free conditions, using grinding
techniques [26]. The last step of this method consists in the cyclodehydration of compounds 4 into
(E)-2-styrylchromones 5, using strong acidic conditions, p-toluenesulfonic acid or a catalytic amount
of iodine in DMSO at 90–100 °C (Scheme 1, step iii) [16–18,25].
A similar procedure is also well-established for the synthesis of flavones. Also in this case the
cyclodehydration reaction of 1-(2-hydroxyphenyl)propane-1,3-diones (which exist also in equilibrium
with their enolic forms) is an important step in the synthesis of flavones using the Baker-Venkataraman
approach (the same sequence presented in Scheme 1, but using benzoic acids instead of cinnamic
acids) [27–29]. This process usually is a catalytic transformation performed in different media. Some
reaction conditions employed an excess of sulfuric acid in glacial acetic acid [30], cationic exchange
resins in isopropyl alcohol [31], CuCl2 in ethanol [32], ionic liquids under microwave irradiation [33],
heteropolyacids, carbon supported triflic acid [34–37] and also grinding techniques in the presence
of phosphorus pentoxide [38]. Some of these methods require high temperatures or long times to
complete the reactions [30,31,37], other require the preparation of the catalysts, involving non-green
and time consuming procedures [34–37], and almost all of them were used to prepare flavones or
simple chromones, but were not used in the synthesis of 2-styrylchromones [30–37]. Pawar and

Molecules 2015, 20
11420
co-workers [33] described the conversion of 1-(2-hydroxyphenyl)-3-phenylpropane-1,3-diones to the
corresponding flavones under microwave irradiation using the ionic liquid [EtNH3]NO3·(EAN).
Despite the structural differences, EAN shares many properties with water [39]. However, while water
is a safe, easily available and relatively low cost and environmentally friendly solvent, the ionic liquid
has to be prepared. EAN is usually synthesized by heating ethyl nitrate with an alcoholic solution of
ammonia or by reacting ethylamine with concentrated nitric acid [40] which cannot be considered
green processes. In addition organic nitrates are potentially explosive, especially when rigorously dried.
The recovery of the ionic liquid requires evaporation of the aqueous layer at 80 °C that represents
additional time and energy consumption.
Scheme 1. Synthesis of (E)-2-styrylchromones by the Baker-Venkataraman method.
The synthesis of flavones using trifluoromethanesulfonic acid supported on carbon as catalyst [37]
was performed using toluene as solvent and requires 5 h for reaction completion. Makrandi and
co-workers [38] described a green synthesis of flavones and 2-styrylchromones via cyclodehydration of
the corresponding 1-(2-hydroxyaryl)-3-(aryl/styryl)propane-1,3-diones under solvent-free conditions in the
presence of phosphorus pentoxide using grinding techniques. However the scope of the reaction was
poorly checked since only substrates containing electron-donating substituents were used.
A different and eco-friendly methodology for the direct synthesis of flavones, from phloroglucinol
and β-ketoesters, was reported by Seijas and co-workers [41]. The reaction involves the cycloaddition
of an α-oxo ketene intermediate followed by an uncatalyzed thermal Fries rearrangement. The flavones
were obtained in very good yields (68%–96%) after 3 min of microwave irradiation using solvent-free
conditions, but the methodology was not extended to the synthesis of 2-styrylchromones. Due to the
formation of polar transition states, the reaction benefits from microwave activation, however 800 W
output power and 240 °C are required to achieve short reaction times and high reaction yields.
Furthermore, when the melting point of the reactants is higher a longer reaction time is required.
Our interest in organic reactions using exclusively water as solvent prompted us to investigate
the aqueous cyclodehydration of appropriate β-diketones to prepare (E)-2-styrylchromones and

Molecules 2015, 20
11421
flavones. The use of water in organic synthesis, without the presence of any organic solvent, can be
beneficial because water is an available, cheap, safe and environmentally benign solvent. So far,
extensive work revealed that a variety of organic reactions including dehydration reactions can be
performed using water as solvent [42–44]. Here we present a protocol for the base-catalyzed
cyclodehydration reaction of compounds 4 and 6 into the corresponding (E)-2-styrylchromones 5 and
flavones 7 in water, in the absence of any organic solvent, and using potassium carbonate as base
(Schemes 1 and 2). The desired compounds 5 and 7 were obtained in yields over 60%, except for
compound 7b. This method represents a cheap, easy and suitable protocol for the cyclodehydration of
5-aryl-1-(2-hydroxyphenyl)pent-4-ene-1,3-diones 4 and 3-aryl-1-(2-hydroxyphenyl)propane-1,3-
diones 6 (which exist in equilibrium with their enolic forms) which contributes to the establishment of
environmentally friendly organic synthesis.
Scheme 2. Cyclodehydration reaction of 3-aryl-1-(2-hydroxyphenyl)propane-1,3-diones
6a,b to flavones 7a,b.
2. Results and Discussion
The typical established methods for the cyclodehydration reaction of 5-aryl-1-(2-
hydroxyphenyl)pent-4-ene-1,3-diones 4 involve the use of strong acidic conditions, p-toluenesulfonic
acid, or a catalytic amount of iodine in DMSO at 90–100 °C [16–18,25]. In order to establish a more
environmental friendly procedure for this cyclodehydration reaction commonly used in our research
group, we performed the base-catalyzed (potassium carbonate) cyclodehydration reaction of 4a in
water. To the best of our knowledge, the cyclodehydration reaction of 5-aryl-1-(2-hydroxyphenyl)pent-
4-ene-1,3-diones 4 in aqueous basic conditions has not been previously reported. Firstly, we performed
the reactions in a small scale (50–200 mg), in order to establish the optimal reaction conditions and to
fully characterize the obtained compounds.
Our results indicate that 0.5 molar equiv of base are enough to perform the expected cyclodehydration
reaction under classical reflux heating (Table 1, Entries 1 and 2). Under these conditions
(E)-2-styrylchromone 5a was obtained in 59% yield. In order to increase the yield, and since the used
β-diketone is not soluble in water, we tried the addition of a phase transfer catalyst (PTC)
(tetrabutylammonium bromide, TBAB) to improve the solubility of 4a. However in the presence of
this catalyst the yield was only 12% (Table 1, Entry 3). We also tried to replace potassium carbonate
by another base, tetramethylammonium hydroxide (TMAOH) as a bifunctional catalyst, acting as base
and as PTC (Table 1, Entries 4 and 5). Since the product was obtained in low yields, we concluded
that the reaction works better in the first conditions, using potassium carbonate as base. Under these
conditions (E)-2-styrylchromones 5b–e were obtained as main compounds in 61%, 70%, 70% and

Molecules 2015, 20
11422
20% yields, respectively (Table 1, Entries 6–9) and two by-products were also identified in each case.
The NMR spectra of the by-product with higher Rf value, obtained in very low yield (less than 10%),
is consistent with a benzalacetone structure, resulting from the hydrolysis of the starting material 4 in
alkaline medium [45]. The other by-product with lower Rf value was identified as the
(E,E)-3-cinnamoyl-2-styrylchromone 8 (see NMR spectra in Supporting Information, Figure S14) and
was obtained in very low yield (less than 5%). A plausible mechanism for the formation of this compound
is similar to the mechanism proposed for the formation of the (E,E)-3-cinnamoyl-2-styrylchromone in
the cyclodehydration of the corresponding 5-aryl-3-hydroxy-1-(2-hydroxyaryl)-2,4-pentadien-1-one,
when performed with a mixture of DMSO and a catalytic amount of iodine at 90 °C [46] (Scheme 3).
H
R
OH
O
O
OH
O
O
H H
OH
O
O
R
R
R
R
4
OH
O
O
OH
O
R
HO
H
R
R
O
O
R
O
O
+
OH
O
OH
O
O
8
Scheme 3. Proposed mechanism for the formation of (E,E)-3-cinnamoyl-2-styrylchromones 8.
Table 1. Cyclodehydration of 5-aryl-1-(2-hydroxyphenyl)pent-4-ene-1,3-diones 4a–e to
(E)-2-styrylchromones 5a–e in water, using classical reflux heating conditions.
Entry
Compound
4a R = H
Base/molar equiv
K2CO3/1
Time (h)
Yield of 5 (%) a
1
2
4 b
58
59
12
19
47
61
70
70
20
4a R = H
K2CO3/0.5
4
3
4a R = H
K2CO3/0.5 + TBAB/0.5
TMAOH/1
3
4
4a R = H
2
5
4a R = H
TMAOH/0.5
K2CO3/0.5
2
6
4b R = OCH3
4c R = Cl
4d R = CH3
4e R = NO2
4a R = H
4
7
K2CO3/0.5
4
8
K2CO3/0.5
4 b
4
9
K2CO3/0.5
10
K2CO3/0.5
4
55 c
a
b
Yields obtained after purification of compounds by thin layer chromatography; Reaction was almost
c
complete after 2 h; Cyclodehydration reaction of 4a was performed on a bigger scale (800 mg). The yield
was determined after filtration of the product precipitate and recrystallization.

Molecules 2015, 20
11423
In order to isolate the product by simple filtration, avoiding the use of the expensive and
time-consuming chromatographic techniques, the cyclodehydration of 4a was performed on a bigger
scale (800 mg) thus establishing an easy scalable protocol. In this case, the yield obtained of 5a was
55%, which was determined through precipitation (after adjustment of pH to 3–4), filtration and
recrystallization of the product 5a (Table 1, Entry 10). Since 2-styrylchromones 5a–e are water
insoluble the scalability of the reaction facilitates the precipitation and product isolation.
To evaluate the effect of microwave radiation in this reaction we performed the base-catalyzed
cyclodehydration reaction of 1-(2-hydroxyphenyl)-5-phenylpent-4-ene-1,3-dione 4a under open and
closed vessel conditions, using water as solvent. Water is a good solvent for microwave assisted
synthesis due to its high dielectric constant [47]. So, we studied the cyclodehydration reaction of 4a
under different temperatures, reaction time and amount of base (results summarized in Table 2). Using
open vessel conditions (reflux, 30 min), the yields for (E)-2-styrylchromones 5a,b,d were 66%, 56%
and 55%, respectively (Table 2, Entries 3, 5 and 9), but this reaction time is not suitable for the
synthesis of (E)-2-styrylchromones with electron-accepting substituents such as 5c,e (Table 2,
Entries 7 and 11). In these cases better yields were obtained (58% and 56%, respectively) after 10 min
of irradiation (Table 2, Entries 6 and 10).
Table 2. Cyclodehydration of 5-aryl-1-(2-hydroxyphenyl)pent-4-ene-1,3-diones 4a–e to
(E)-2-styrylchromones 5a–e in water, under microwave irradiation, using open vessel
reflux and closed vessel (120 °C) conditions.
Entry
1
Compound
4a R =H
Method
Open
Base/molar equiv
K2CO3/1
Time (min)
Yield of 5 (%) a
10
5
35
54
66
47
56
58
47
45
55
56
38
50
67
77
66
38
41
57
27
60
2
4a R =H
Open
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
K2CO3/0.5
TMAOH/0.5
3
4a R = H
Open
30
10
30
10
30
10
30
10
30
5
4
4b R = OCH3
4b R = OCH3
4c R = Cl
Open
5
Open
6
Open
7
4c R = Cl
Open
8
4d R = CH3
4d R = CH3
4e R = NO2
4e R = NO2
4a R =H
Open
9
Open
10
11
12
13
14
15
16
17
18
19
20
Open
Open
Closed
Closed
Closed
Closed
Closed
Closed
Closed
Closed
Closed
4a R = H
30
30
10
15
30
30
30
10
4b R = OCH3
4c R = Cl
4c R = Cl
4c R = Cl
4d R = CH3
4e R = NO2
4e R = NO2
a Yields obtained after purification of compounds by thin layer chromatography.

Molecules 2015, 20
11424
Employing closed vessel conditions (120 °C, 30 min) compounds 5a,b,d were obtained in 67%,
77% and 57% yields, respectively (Table 2, Entries 13, 14 and 18). For compounds 5c,e we observed
a high degradation in the reaction mixture after 30 min of closed vessel microwave conditions (Table 2,
Entries 17 and 19), but good yields (66% and 60%, respectively) were obtained only with 10 min of
irradiation (Table 2, Entries 15 and 20). In the case of the cyclodehydration of derivative 4e, TMAOH
was used as base and as PTC in order to improve the solubility of this compound in water which led to
the formation of compound 5e in 60% yield (Table 2, Entry 20).
We also performed the reaction with a lower amount of K2CO3 (0.05 equiv) using closed vessel
microwave conditions. In a first attempt the cyclodehydration of 4a was performed at 120 °C for
30 min; however the 2-styrylchromone 5a was obtained in 16% yield and 26% of 4a was recovered.
In order to improve the yield, we repeated the reaction at 200 °C (for 30 min). Under these conditions,
compounds 5a–e were obtained in 64%–75% yield (Table 3).
Table 3. Cyclodehydration of 5-aryl-1-(2-hydroxyphenyl)pent-4-ene-1,3-diones 4a–e to
(E)-2-styrylchromones 5a–e in water and in the presence of a catalytic amount of K2CO3,
using closed vessel microwave conditions, at 200 °C.
Entry
Compound
4a R = H
Base/molar equiv
K2CO3/0.05
K2CO3/0.05
K2CO3/0.05
K2CO3/0.05
K2CO3/0.05
Time (min)
Yield of 5 (%) a
1
2
3
4
5
30
30
30
30
30
65
75
64
68
69
4b R = OCH3
4c R = Cl
4d R = CH3
4e R = NO2
a Yields obtained after purification of compounds by thin layer chromatography.
Comparing the results obtained in classical and microwave heating methods, a significant reduction
of the reaction time was achieved from 2–4 h (classical heating) to 10–30 min (microwave heating).
In addition, we demonstrated that it is possible to use a catalytic amount of base (0.05 equiv) using
rapid microwave heating at a substantially higher temperature (at 200 °C), taking advantage of the use
of water under closed vessel microwave conditions.
Recently, a new synthetic route of flavones was reported, consisting in a one-pot procedure by
treatment of 2′-hydroxyacetophenones with 3 molar equiv of aroyl chloride in net K2CO3/acetone
(1% w/w water) [48]. Under these conditions flavones were obtained in 51%–65% yields together with
3-aroylflavones (11%–23%); this study was not extended to the synthesis of 2-styrylchromones.
After establishing the best conditions for the base-catalyzed cyclodehydration reaction of
5-aryl-1-(2-hydroxyphenyl)pent-4-ene-1,3-diones 4a–e under classical reflux heating and microwave
irradiation, we extended our study to other 3-aryl-1-(2-hydroxyphenyl)propane-1,3-diones 6a,b in
order to prepare flavones 7a,b (Scheme 2, Table 4). Cyclodehydration of compound 6a occurs in
excellent yield (quantitative yield) in both classical reflux heating for 1 h and under microwave
irradiation for 30 min (Table 4, Entries 1 and 3). In the case of compound 6b the reaction was
performed only under closed vessel microwave conditions. After 15 min of irradiation some unreacted
starting material was observed while after 30 min the expected flavone 7b was obtained in 45% yield
(Table 4, Entry 4). However after longer reaction time (45 min) the yield was not improved (46% yield)

Molecules 2015, 20
11425
due to high degradation in the reaction mixture (Table 4, Entry 5). These results indicate that the
substituents on the diketone structure have a great effect on the yield of the cyclodehydration reaction.
Table 4. Cyclodehydration reaction of 3-aryl-1-(2-hydroxyphenyl)propane-1,3-diones 6a,b
into flavones 7a,b, under classical reflux heating and closed vessel microwave conditions,
at 200 °C.
Entry
Compound
Method
Oil bath
Reaction Time (min)
Yield of 7 (%) a
1
2
3
4
5
6a R1 =CH3, R2 = H
6a R1 =CH3, R2 = H
6a R1 =CH3, R2 = H
6b R1 =H, R2 = OBn
6b R1 =H, R2 = OBn
60
15
30
30
45
Quantitative
Microwave
Microwave
Microwave
Microwave
70
Quantitative
45
46
a Yields obtained after purification of compounds by thin layer chromatography.
A plausible mechanism for the formation of 2-styrylchromones 5a–e and flavones 7a,b under the
described experimental conditions is proposed in Scheme 4. Enolization of the α-carbonyl group
in 4 or 6, leads to intermediate 9 in the presence of a base (K2CO3), and intramolecular cycloaddition
of 9 gives 10. Rearomatization of 10 by elimination of KOH provides the corresponding products 5 or 7.
A similar mechanism was proposed by Fu and coworkers for the synthesis of chromones by
K2CO3-catalysed (0.20 equiv) intramolecular cyclization of the corresponding diketones in DMF [49].
Scheme 4. Possible mechanism on base-catalyzed cyclodehydration of β-diketones 4a–e
and 6a,b in water.
3. Experimental Section
3.1. General Information
Melting points were determined on a Büchi B-545 melting point apparatus. Preparative thin-layer
chromatography when used was carried out with Merck silica gel (60 DGF254). NMR spectra were
1
13
recorded on a Bruker Avance 300 spectrometer (300.13 MHz for H and 75.47 MHz for C), with
CDCl3 used as solvent if not stated otherwise. The internal standard was TMS (see Supporting
Information). Microwave-assisted reactions were carried out in a CEM Discovery Labmate circular
single-mode cavity instrument (300 W max magnetron power output) from CEM Corporation.
Reactions carried out in open vessel were performed using a 50 mL round-bottom flask filled with

Molecules 2015, 20
11426
the reaction mixture and equipped with a condensator under nitrogen atmosphere. Reactions carried
out in closed vessel were performed in a sealed 10 mL vessel and 100 psi of pressure was defined as
the limit to operate in safe conditions. In open and closed vessel conditions the temperature was always
controlled using the vertically focused IR temperature sensor (40–300 °C temperature range) of the
CEM monomode microwave, for volume-independent non-invasive temperature measurement.
3.2. Optimized Experimental Procedure for the Cyclodehydration Reaction of β-Diketones 4a–e and
6a under Classical Heating Conditions
Potassium carbonate (52.52 mg, 0.38 mmol) was added to the appropriate β-diketone 4a–e or 6a
(0.75 mmol) in distilled water (10–15 mL). The mixture was refluxed under nitrogen atmosphere for
(2–4 h, see Table 1) until the consumption of starting material (the reaction progress was monitored by
tlc). After that period, the mixture was acidified at pH 3–4 with a 20% HCl solution and the obtained
product extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried with
anhydrous sodium sulfate and concentrated under reduced pressure. In some cases the obtained
compound was purified by thin layer chromatography using dichloromethane as eluent. When the
reaction was performed in a bigger scale (3.0 mmol) the product precipitates after acidification at pH
3–4 and was isolated by filtration and recrystallized from ethanol. Compounds were obtained as yellow
solids (5a, 109.9 mg, 59%; 5b, 127.3 mg, 61%; 5c, 148.4 mg, 70%; 5d, 137.7 mg, 70%; 5e, 44.0 mg,
20%), or white solids (7a, 177.2 mg, quantitative yield).
3.3. Optimized Experimental Procedure for the Cyclodehydration Reaction of β-Diketones 4a–e under
Microwave Irradiation in Open Vessels
Potassium carbonate (52.52 mg, 0.38 mmol) was added to the appropriate β-diketone 4a–e
(0.75 mmol) in distilled water (7 mL). The mixture was refluxed under microwave irradiation using
a 50 mL round-bottom flask equipped with a condenser under nitrogen atmosphere (for reaction time
see Table 2). After that period, the mixture was acidified at pH 3–4 with a 20% HCl solution and
the product was extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried with
anhydrous sodium sulfate and concentrated under reduced pressure. In some cases the obtained
compound was purified by thin layer chromatography using dichloromethane as eluent. Compounds
were obtained as yellow solids (5a, 122.9 mg, 66%; 5b, 116.9 mg, 56%; 5c, 123.0 mg, 58%; 5d, 108.2
mg, 55%; 5e, 123.2 mg, 56%).
3.4. Optimized Experimental Procedure for the Cyclodehydration Reaction of β-Diketones 4a–e and
6a,b under Microwave Irradiation in Closed Vessels
The appropriate amount of potassium carbonate (0.5 equiv or 0.05 equiv) was added to the
appropriate β-diketone 4a–e or 6a,b (0.19 mmol) in distilled water (3.5 mL). The mixture was heated
at 120 °C or 200 °C in a 10 mL closed vessel under microwave irradiation (for reaction time see
Tables 2–4). After that period, the mixture was acidified at pH 3–4 with a 20% HCl solution and the
product was extracted with ethyl acetate (3 × 50 mL). The combined organic layer was dried with
anhydrous sodium sulfate and concentrated under reduced pressure. In some cases the obtained

Molecules 2015, 20
11427
compound was purified by thin layer chromatography using dichloromethane as eluent. Compounds
were obtained as yellow solids (at 120 °C: 5a, 31.6 mg, 67%; 5b, 40.7 mg, 77%; 5c, 35.4 mg, 66%; 5d,
28.4 mg, 57%; 5e, 33.4 mg, 60%. At 200 °C: 5a, 30.7 mg, 65%; 5b, 39.7 mg, 75%; 5c, 34.4 mg, 64%;
5d, 33.9 mg, 68%; 5e, 38.4 mg, 69%) or white solids (7a, 44.9 mg, quantitative yield; 7b, 28.7 mg,
46%). The melting points of compounds 5a–e and 7a,b were determined and compared with those
reported in the literature [50–53] (Tables 5 and 6). Due to the difference between the measured melting
points and those from the literature for compounds 5b and 7a, 3 samples of each one of these
compounds, obtained in three different experiments, were taken, analyzed by NMR and the
corresponding melting points were determined. All the samples were dried on a vacuum line. For all
the three experiments the structure and purity of compounds 5b and 7a was confirmed by NMR. The
experimental melting points were always around 125–126 °C for 5a and 73–74 °C for 7a and very
different from that reported on the literature 139–140 °C and 110–112 °C, respectively.
Table 5. Yield and melting point data of the compounds 5a–e.
Compounds
R
H
Yield
67
Melting Point (°C)
136–137
Melting Point (°C) (Lit.) [50,51]
5a
5b
5c
5d
5e
133–134
139–140 a
224–226
159–160
282–283
OCH3
Cl
77
125–126
70
218–219
CH3
70
158–159
NO2
60
276–278
a This compound was synthesized and characterized three times. The NMR data proved the structure and the
determined melting point was the same in the three determinations.
Table 6. Yield and melting point data of the compounds 7a,b.
Compounds
R1
CH3
H
R2
H
Yield
Quant.
46
Melting Point (°C)
73–74
Melting Point (°C) (Lit.)
110–112 a [52]
7a
7b
OBn
82–84
82–83 [53]
a This compound was synthesized and characterized three times. The NMR data proved the structure and the
determined melting point was the same in the three determinations.
4. Conclusions
A new methodology for the cyclodehydration reaction of the appropriate β-diketones to prepare
a variety of (E)-2-styrylchromones and flavones in good yields (67%–75%) and (46% to quantitative
yield), respectively, was established. Comparing to the yields obtained using the usual established
methods (69%–94%) [47,48], our yields are similar as well as the compounds’ purity. The use of water
as a solvent, offers significant environmental advantages and facilitates the isolation and purification
of the products when compared with the DMSO, which is the solvent typically use in such reactions.
Furthermore, this new methodology should allow the easy scale up of the reaction being cheaper, safe
and more environmentally friendly than the traditional methods.

Molecules 2015, 20
11428
Supplementary Materials
13
1H- and C-NMR spectra of compounds 5a–e (Figures S1–S9) and 7a,b (Figures S10–S13) and
1H-NMR spectrum of compound 8 (Figure S14). Supplementary materials can be accessed at:
http://www.mdpi.com/1420-3049/20/6/11418/s1.
Acknowledgments
Thanks are due to the University of Aveiro, “Fundação para a Ciência e a Tecnologia” (FCT,
Portugal), European Union, QREN, FEDER and COMPETE for funding the QOPNA (Ref
UID/QUI/00062/2013) research unit, the project QREN (FCOMP-01-0124-FEDER-010840-
PTDC/QUI-QUI/102454/2008) and the Portuguese National NMR network. Vera L.M. Silva thanks
the project New Strategies Applied to Neuropathological Disorders (CENTRO-07-ST24-FEDER-
002034), co-funded by QREN, “Mais Centro-Programa Operacional Regional do Centro” and EU,
FEDER for her Assistant Research position, while Joana Pinto thanks FCT for her PhD grant
(SFRH/BD/77807/2011).
Author Contributions
V.L.M.S. (principal investigator of the project FCOMP-01-0124-FEDER-010840-PTDC/QUI-
QUI/102454/2008), A.M.G.S. and A.M.S.S. designed research and wrote the paper; J.P. performed the
work under the supervision of V.L.M.S. A.M.G.S. collaborate in the supervision of the microwave.
V.L.M.S. and A.M.G.S. analysed all the results.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Cook, C.; Samman, S. Flavonoids-chemistry, metabolism, cardioprotective effects, and dietary
sources. J. Nutr. Biochem. 1996, 7, 66–76.
2. Alam, S. Synthesis, antibacterial and antifungal activity of some derivatives of
2-phenyl-chromen-4-one. J. Chem. Sci. 2004, 116, 325–331.
3. Cushnie, T.P.T.; Lamb, A.J. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents 2005, 26,
343–356.
4. Wu, J.; Wang, X.; Yi, Y.; Lee, K. Anti-AIDS agents 54. A potent anti-HIV chalcone and
flavonoids from genus Desmos. Bioorg. Med. Chem. Lett. 2003, 13, 1813–1815.
5. Kim, J.Y.; Lim H.J.; Ryu, J.-H. In vitro anti-inflammatory activity of 3-O-methyl-flavones
isolated from Siegesbeckia glabrescens. Bioorg. Med. Chem. Lett. 2008, 18, 1511–1514.
6. Rice-Evans, C. Flavonoid antioxidants. Curr. Med. Chem. 2001, 8, 797–807.
7. Yamamura, S.; Ozawa, K.; Ohtani, K.; Kasai, R.; Yamasaki, K. Antihistaminic flavones and
aliphatic glycosides from Mentha spicata. Phytochemistry 1998, 48, 131–136.

Molecules 2015, 20
11429
8. Liu, Y.-T.; Lu, B.-N.; Peng, J.-Y. Hepatoprotective activity of the total flavonoids from Rosa
laevigata Michx fruit in mice treated by paracetamol. Food Chem. 2011, 125, 719–725.
9. Martens, S.; Mithöfer, A. Flavones and flavone synthases. Phytochemistry 2005, 66, 2399–2407.
10. Cárdenas, M.; Marder, M.; Blank, V.C.; Roguin, L.P. Antitumor activity of some natural flavonoids
and synthetic derivatives on various human and murine cancer cell lines. Bioorg. Med. Chem.
2006, 14, 2966–2971.
11. Gerwick, W.H.; Lopez, A.; van Duyne, G.D.; Clardy, J.; Ortiz, W.; Baez, A. Hormothamnione,
a novel cytotoxic styrylchromone from the marine cyanophyte hormothamnion enteromorphoides
grunow. Tetrahedron Lett. 1986, 27, 1979–1982.
12. Gerwick, W.H. 6-Desmethoxyhormothamnione, a new cytotoxic styrylchromone from the marine
cryptophyte Chrysophaeum taylori. J. Nat. Prod. 1989, 52, 252–256.
13. Yoon, J.S.; Lee, M.K.; Sung, S.H.; Kim, Y.C. Neuroprotective 2-(2-phenylethyl)chromones of
Imperata cylindrical. J. Nat. Prod. 2006, 69, 290–291.
14. Yang, L.; Qiao, L.; Xie, D.; Yuan, Y.; Chen, N.; Dai, J.; Guo, S. 2-(2-Phenylethyl)chromones
from Chinese eaglewood. Phytochemistry 2012, 76, 92–97.
15. Yang, C.-H.; Yang, Y.; Liu, J.-H. Platachromone A–D: Cytotoxic 2-styrylchromones from the
bark of Platanus × acerifolia (Aiton) Willd. Phytochem. Lett. 2013, 6, 387–391.
16. Silva, A.M.S.; Pinto, D.C.G.A.; Cavaleiro, J.A.S.; Lévai, A.; Patonay, T. Synthesis and reactivity
of styrylchromones. Arkivoc 2004, vii, 106–123.
17. Gomes, A.; Freitas, M.; Fernandes, E.; Lima, J.L.F.C. Biological activity of 2-styrylchromones.
Mini Rev. Med. Chem. 2010, 10, 1–7.
18. 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.
19. Shaw, A.Y.; Chang, C.Y.; Liau, H.H.; Lu, P.J.; Chen, H.L.; Yang, C.N.; Li, H.Y. Synthesis of
2-styrylchromones as a novel class of antiproliferative agents targeting carcinoma cells. Eur. J.
Med. Chem. 2009, 44, 2552–2562.
20. Doria, G.; Romeo, C.; Forgione, A.; Sberze, P.; Tibolla, N.; Corno, M.L.; Cruzzola, G.; Cadelli, G.
Antiallergic agents. III. Substituted trans-2-ethenyl-4-oxo-4H-1-benzopyran-6-carboxylic acids.
Eur. J. Med. Chem. 1979, 14, 347–351.
21. Conti, C.; Mastromarino, P.; Goldoni, P.; Portalone, G.; Desideri, N. Synthesis and anti-rhinovirus
properties of fluoro-substituted flavonoids. Antivir. Chem. Chemother. 2005, 16, 267–276, and
references cited therein.
22. Fernandes, E.; Carvalho, F.; Silva, A.M.S.; Santos, C.M.M.; Pinto, D.C.G.A.; Cavaleiro, J.A.S.;
Bastos, M.L. 2-Styrylchromones as novel inhibitors of xanthine oxidase. A structure-activity
study. J. Enzym. Inhib. Med. Chem. 2002, 17, 45–48.
23. Fernandes, E.; Carvalho, M.; Carvalho, F.; Silva, A.M.S.; Santos, C.M.M.; Pinto, D.C.G.A.;
Cavaleiro, J.A.S.; Bastos, M.L. Hepatoprotective activity of polyhydroxylated 2-stryrylchromones
against tert-butylhydroperoxide induced toxicity in freshly isolated rat hepatocytes. Arch. Toxicol.
2003, 77, 500–505.

Molecules 2015, 20
11430
24. Filipe, P.; Silva, A.M.S.; Morliere, P.; Brito, C.M.; Patterson, L.K.; Hug, G.L.; Silva, J.N.;
Cavaleiro, J.A.S; Maziere, J.C.; Freitas, J.P.; et al. Polyhydroxylated 2-styrylchromones as potent
antioxidants. Biochem. Pharmacol. 2004, 67, 2207–2218, and references cited therein.
25. Pinto, D.C.G.A.; Silva, A.M.S.; Cavaleiro, J.A.S. A convenient synthesis of new
(E)-5-hydroxy-2-styrylchromones by modifications of the Baker-Venkataraman method. New J.
Chem. 2000, 24, 85–92.
26. Sharma, D.; Kumar, S.; Makrandi, J.K. Solid phase Baker-Venkataraman rearrangement under
solvent-free condition using grinding technique. Green Chem. Lett. Rev. 2009, 2, 53–55.
27. Baker, W. Molecular rearrangement of some o-acyloxyacetophenones and the mechanism of the
production of 3-acylchromones. J. Chem. Soc. 1933, 1381–1389.
28. Mahal, H.S.; Venkataraman, K. Synthetical experiments in the chromone group. Part XIV. The
action of sodamide on 1-acyloxy-2-acetonaphthones. J. Chem. Soc. 1934, 1767–1769.
29. Mughal, E.U.; Ayaz, M.; Hussain, Z.; Hasan, A.; Sadiq, A.; Riaz, M.; Malik, A.; Hussain, S.;
Choudhary, M.I. Synthesis and antibacterial activity of substituted flavones, 4-thioflavones and
4-iminoflavones. Bioorg. Med. Chem. 2006, 14, 4704–4711, and references cited therein.
30. Wheeler, T. Flavone. Org. Synth. 1952, 32, 72–76.
31. Hoshino, Y.; Takeno, N. A facile preparation of flavones using non aqueous cation-exchange
resin. Bull. Chem. Soc. Jpn. 1987, 60, 1919–1920.
32. Kabalka, G.W.; Mereddy, A.R. Microwave-assisted synthesis of functionalized flavones and
chromones. Tetrahedron Lett. 2005, 46, 6315–6317.
33. Sarda, S.; Pathan, M.; Paike, V.; Pachmase, P.; Jadhav, W.; Pawar, R. A facile synthesis of
flavones using recyclable ionic liquid under microwave irradiation. ARKIVOC 2006, xvi, 43–48.
34. Bennardi, D.O.; Romanelli, G.P.; Jios, J.L.; Autino, J.C.; Baronetti, G.T.; Thomas, H.J. Synthesis of
substituted flavones and chromones using a Wells-Dawson heteropolyacid as catalyst. ARKIVOC
2008, xi, 123–130.
35. Bennardi, D.O.; Ruiz, D.M.; Romanelli, G.P.; Baronetti, G.T.; Thomas, H.J.; Autino, J.C.
Efficient microwave solvent-free synthesis of flavones, chromones, coumarins and dihydrocoumarins.
Lett. Org. Chem. 2009, 5, 607–615.
36. Romanelli, G.; Virla, E.; Duchowicz, P.; Gaddi, A.; Ruiz, D.; Bennardi, D.; Dell Valle Ortiz, D.;
Autino, J. Sustainable synthesis of flavonoid derivatives, QSAR study and insecticidal activity
against the fall armyworm, Spodoptera frugiperda (Lep.: Noctuidae). J. Agric. Food Chem. 2010, 8,
6290–6295.
37. Bennardi, D.O.; Romanelli, G.P.; Autino, J.C.; Pizzio, L.R. Trifluoromethanesulfonic acid supported
on carbon used as catalysts in the synthesis of flavones and chromones. Catal. Commun. 2009, 10,
576–581.
38. Sharma, D.; Makrandi, J.K. A green synthesis of 2-phenyl/2-styrylchromones under solvent-free
conditions using grinding technique. Green Chem. Lett. Rev. 2009, 2, 157–159.
39. Allen, M.; Evans, D.F.; Lumry, R. Thermodynamic Properties of the Ethylammonium Nitrate + Water
System: Partial Molar Volumes, Heat Capacities, and Expansivities. J. Solut. Chem. 1985, 14,
549–560.

Molecules 2015, 20
11431
+
40. Aridoss, G.; Laali, K.K. Building Heterocyclic Systems with RC(OR)2 Carbocations in Recyclable
Brønsted Acidic Ionic Liquids: Facile Synthesis of 1-Substituted 1H-1,2,3,4-Tetrazoles, Benzazoles
and Other Ring Systems with CH(OEt)3 and EtC(OEt)3 in [EtNH3][NO3] and [PMIM(SO3H)][OTf].
Eur. J. Org. Chem. 2011, 2011, 2827–2835.
41. Seijas, J.A.; Vázquez-Tato, M.P.; Carballido-Reboredo, R. Solvent-Free Synthesis of Functionalized
Flavones under Microwave Irradiation. J. Org. Chem. 2005, 70, 2855–2858.
42. Breslow, R. Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res. 1991, 24,
159–164.
43. Li, C.-J. Organic reactions in aqueous media with a focus on carbon-carbon bond formations:
A decade update. Chem. Rev. 2005, 105, 3095–3165.
44. Horváth, I.T. Solvents from nature. Green Chem. 2008, 10, 1024–1028.
45. Hauser, C.R.; Swamer, F.W.; Ringler, B.I. Alkaline cleavage of unsymmetrical β-diketones. Ring
opening of acylcylohexanones to form ε-acyl caproic acids. J. Am. Chem. Soc. 1948, 70, 4023–4026.
46. Santos, C.M.M.; Silva, A.M.S.; Cavaleiro, J.A.S. Synthesis of new hydroxy-2-styrylchromones.
Eur. J. Org. Chem. 2003, 4575–4585.
47. Dallinger, D.; Kappe, C.O. Microwave-assisted synthesis in water as solvent. Chem. Rev. 2007, 107,
2563–2591.
48. Chee, C.F.; Buckle, M.J.C.; Rahman, N.A. An efficient one-pot synthesis of flavones.
Tetrahedron Lett. 2011, 52, 3120–3123.
49. Zhao, J.; Zhao, Y.; Fu, H. K2CO3-Catalyzed synthesis of chromones and 4-quinolones through the
cleavage of aromatic C-O bonds. Org. Lett. 2012, 14, 2710–2713.
50. Pinto, D.C.G.A.; Silva, A.M.S.; Almeida, L.M.P.M.; Cavaleiro, J.A.S.; Lévai, A.; Patonay, T.
Synthesis of 4-aryl-3-(2-chromonyl)-2-pyrazolines by the 1,3-dipolar cycloaddition of
2-styrylchromones with diazomethane. J. Heterocycl. Chem. 1998, 35, 217–224.
51. Barros, A.I.R.N.A.; Silva, A.M.S. Synthesis and structure elucidation of three series of
nitro-2-styrylchromones using 1D and 2D NMR spectroscopy. Magn. Reson. Chem. 2009, 47,
885–896.
52. Jayashree, B.S.; Alam, A.; Nayak, Y.; Kumar, D.V. Synthesis of 3-methylflavones and their
antioxidant and antibacterial activities. Med. Chem. Res. 2012, 21, 1991–1996.
53. Riva, C.; De Toma, C.; Donadel, L.; Boi, C.; Pennini, R.; Motta, G.; Leonardi, A.
New DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) assisted one-pot synthesis of 2,8-disubstituted
4H-1-benzopyran-4-ones. Synthesis 1997, 195–201.
Sample Availability: Samples of the compounds 4a–e, 5a–e, 6a,b and 7a,b are available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).