Coumarin derivatives solvent-free synthesis under microwave irradiation over heterogeneous solid catalysts

Article abstract of DOI:10.3390/molecules22122072

A suitable methodology of synthesis of coumarin derivatives by Pechmann reaction over heterogeneous solid acid catalysts in a free solvent media under microwave irradiation is described. Resorcinol, phenol and ethyl acetoacetate were selected as model reactants in the Pechmann condensation. The catalytic activity of several materials—Amberlyst-15, zeolite β and sulfonic acid functionalized hybrid silica—in solvent-free microwave-assisted synthesis of the corresponding coumarin derivatives has been investigated in detail. 7-Hydroxy-4-methylcoumarin and 4-methylcoumarin were obtained in 97% and 43% yields, respectively, over Amberlyst-15. This was the most active catalyst in the Pechmann reaction under studied conditions.

Full text of DOI:10.3390/molecules22122072

molecules
Article
Coumarin Derivatives Solvent-Free Synthesis under
Microwave Irradiation over Heterogeneous
Solid Catalysts
Souad Bouasla 1,2,3,*, Juan Amaro-Gahete 2 ID , Dolores Esquivel 2,
*
ID , M. Isabel López 2,
César Jiménez-Sanchidrián 2, Mabrouk Teguiche 3 and Francisco J. Romero-Salguero 2,
*
ID
1
Skikda Higher School of Technological Education, Azzaba 21300, Algeria
2
Departamento de Química Orgánica, Instituto Universitario de Investigación en Química Fina y
Nanoquímica IUIQFN, Facultad de Ciencias, Universidad de Córdoba, Campus de Rabanales,
Edificio Marie Curie, E-14071 Córdoba, Spain; q22amgaj@uco.es (J.A.-G.);
marisa_lopez_martinez@hotmail.com (M.I.L.); qo1jisac@uco.es (C.J.-S.)
Applied Chemistry Laboratory (ACL), Faculty of Mathematics, Informatics and Materials Sciences,
Department of Materials Science, Guelma 24000, Algeria; teghichemab@yahoo.fr
3
*
Correspondence: souad2004_chem@yahoo.fr (S.B.); q12esmem@uco.es (D.E.); qo2rosaf@uco.es (F.J.R.-S.);
Tel.: +213-38-959-681 (S.B.); +34-957-211-050 (D.E.); +34-957-218-638 (F.J.R.S.)
Received: 31 October 2017; Accepted: 23 November 2017; Published: 28 November 2017
Abstract: A suitable methodology of synthesis of coumarin derivatives by Pechmann reaction
over heterogeneous solid acid catalysts in a free solvent media under microwave irradiation is
described. Resorcinol, phenol and ethyl acetoacetate were selected as model reactants in the
Pechmann condensation. The catalytic activity of several materials—Amberlyst-15, zeolite
β and
sulfonic acid functionalized hybrid silica—in solvent-free microwave-assisted synthesis of the
corresponding coumarin derivatives has been investigated in detail. 7-Hydroxy-4-methylcoumarin
and 4-methylcoumarin were obtained in 97% and 43% yields, respectively, over Amberlyst-15.
This was the most active catalyst in the Pechmann reaction under studied conditions.
Keywords: phenol; ethyl acetoacetate; solvent-free; microwave irradiation; heterogeneous acid catalysts
1. Introduction
Coumarins are an important family of oxygen-containing heterocycles with a 1-benzopyran-2-one
moiety, originally found as secondary metabolites in some plants (Rutaceae and Umbelliferae family)
and microorganisms [
including antibacterial [
and anti-HIV [ ], among others [10
1
]. Coumarin derivatives have displayed widespread therapeutic applications
], anti-inflammatory [ ], antioxidant [ ], anticoagulant [ ], anticancer [
11]. Additionally, these compounds have attracted a great interest
2,
3
4
5
6
7,8]
9
,
in other fields, such as fragrance and cosmetic [12], agrochemical [13], food and dyes industries [14].
Due to their applicability, several methods have been developed over the years to synthesize
coumarin derivatives such as Pechmann condensation [15], Knoevenagel [16], Perkin, Witting,
Reformantsky reactions and by flash vacuum pyrolysis [17] or via carbon suboxide [18]. Among these
methods, the Pechmann reaction is a simple and widely used method for the synthesis of 4-substituted
coumarins, since it requires simple and inexpensive starting materials, i.e., phenols and β-ketoesters.
This reaction proceeds in acidic media, using either homogenous Brönsted acid catalysts like H2SO4,
HCl, H3PO4 and CF3COOH [19] or Lewis acid catalysts such as InCl3, Sm (NO3)3, ZrCl4, BiCl3 and
FeF3, among others [20–23]. However, these catalysts require drastic conditions, long reaction times
and large quantities to reach high yields. In addition, they are corrosive, hard to remove from the
reaction mixture, non recoverable and pollutants for the environment.
Molecules 2017, 22, 2072; doi:10.3390/molecules22122072
www.mdpi.com/journal/molecules

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Recently, a number of heterogeneous solid acid catalysts like, Nafion-H, zeolite H-BEA [24],
montmorillonite clays [25], ionic liquids [26], Nafion resin/silica nano-composites [27], silica supported
perchloric acid (HClO4
acid [29], ZrOCl2 8H2O/SiO2 [30], and many more have been employed to replace classical acids in
Pechmann condensation [31 33]. The use of heterogeneous acid catalysts presumes advantages
·
SiO2) [28], mesoporous zirconium phosphate (m-ZrP) [28], cellulose sulfuric
·
–
like their easy recovery by simple filtration, reusability, less corrosion issues, minimized waste
contamination and environmental-friendliness.
On the other hand, in recent years, the concept of speeding up the synthetic transformations by
microwave activation has created a lot of interest in organic synthesis [34]. The coupling of microwave
heating under solvent-free conditions in chemical processeses catalyzed by solids gives rise to an
enhancement of the reaction rate, ease of work-up and high yields [35].
The aim of this work is the optimization of a suitable methodology to yield coumarin
derivatives under solvent-free conditions using microwave irradiation. The catalytic activity of
several heterogeneous solid acid catalysts in the Pechmann reaction of phenols (resorcinol and phenol)
with ethyl acetoacetate to produce 7-hydroxy-4-methyl coumarin and 4-methylcoumarin, respectively,
has been studied in detail.
2. Results
Firstly, resorcinol and ethyl acetoacetate were employed as the model reactants in the Pechmann
condensation under microwave reaction. Resorcinol (1,3-dihydroxybenzene) was chosen due to its
high reactivity (Scheme 1).
Scheme 1.
Pechmann reaction of resorcinol (1) with ethyl acetoacetate (2) to produce
7-hydroxy-4-methylcoumarin (3).
Commercial sulfonic acid resin, Amberlyst-15, was employed to evaluate the reaction kinetic
with the above-mentioned reactants (1:1 molar ratio) at 100 ◦C. After 5 min of microwave irradiation,
Amberlyst-15 showed a conversion of around 83%. By varying the reaction time from 5 min to 20 min,
a maximum yield of 97% was obtained (Table 1). No reaction was observed in the absence of catalyst
(blank reaction).
Table 1. Condensation reaction of resorcinol with ethyl acetoacetate using various heterogeneous solid
acids catalysts 1.
2
−1
−1
Acidity (mmol g )
Catalyst
SBET (m2g
)
Yield (%)
Amberlyst-15
H-β
TS-OS-SO3H
43
530
448
4.30
1.01
1.24
97
21
44
1
Reaction conditions: Molar ratio (resorcinol/ethyl acetoacetate) = 1:1, catalyst amount = 0.050 g, temperature =
100 ◦C, reaction time = 20 min. Specific surface area determined using the BET (Brunauer-Emmett-Teller) method
2
over a relative pressure (P/P0) range of 0.05–0.30.
The catalytic behavior of Amberlyst-15 in the synthesis of 7-hydroxy-4-methylcoumarin was
compared with other acid solid catalysts, such as zeolite H-
β and sulfonic acid functionalized
hybrid material (TS-OS-SO3H). The results are summarized in Table 1. Amberlyst-15 catalyst
exhibited much higher yield of 7-hydroxy-4-methylcoumarin than the other catalysts after 20 min of

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reaction. Compared with the Amberlyst-15, the H-
β
and TS-OS-SO3H materials contained fewer
acid sites per gram of catalyst (Table 1). In general, the catalytic activity on the synthesis of
7-hydroxy-4-methylcoumarin could be related to the amount of acid sites [36]. However, the sulfonic
acid functionalized hybrid silica with an acidity of 1.24 mmol H g−1, four times lower than
Amberlyst-15, exhibited a yield higher than expected. This suggests that not all sites in the interior
of the resin are accessible to the reactants. Additionally, this phenomenon could explain the double
yield (44%) obtained over TS-OS-SO3H in comparison with the corresponding
β zeolite (21%).
Despite a similar value of BET surface area and acidity (Table 1), probably the diffusion of resorcinol,
a meta-hydroxy substituted phenol, is hindered through the zeolitic channels [27]. Another zeolite
with higher Si/Al ratio (zeolite H-β, Si/Al = 75) was evaluated in this reaction. This showed similar
conversion to H-β, which indicated that hydrophobicity does not have any important role in this type
of reaction [37].
It is well known that, of the simple mono-, di-, and tri-hydric phenols, resorcinol is the most
reactive, and it easily condenses with many substituted and cyclic -ketonic esters. Unlike resorcinol,
β
phenol exhibits low reactivity giving only ca. 3% yield of 4-methylcoumarin on the Pechmann reaction
with ethyl acetoacetate in the presence of sulfuric acid [38]. Earlier reports on microwave-assisted
solvent-free synthesis of 4-methylcoumarin using nano-crystalline sulfated-zirconia catalyst did not
show product formation under the studied conditions [39]. Due to the scarce studies of the synthesis
of 4-methylcoumarin, phenol was selected as the reactant model to optimize the experimental catalytic
conditions under microwave irradiation.
2.1. Optimization of Reaction Conditions
The Pechmann condensation of phenol and ethyl acetoacetate to afford 4-methylcoumarin on
microwave-assisted solvent-free conditions was studied using different acid heterogeneous catalysts
(Scheme 2). Initially, the experimental conditions such as the amount of catalyst and temperature
reaction were optimized over Amberlyst-15.
Scheme 2. Synthesis of 4-methylcoumarin (
acetoacetate (2).
3) via the Pechmann condensation of phenol (1) and ethyl
To optimize the amount of catalyst, the Pechmann condensation between phenol and ethyl
acetoacetate was carried out under solvent-free conditions over Amberlyst-15 catalyst for 20 min at
100 ◦C using a molar ratio of phenol: Ethyl acetoacetate of 1:1. As can be observed, the conversion
of phenol gradually increased from 3.8% to 21.5% with increasing the amount of catalyst from 0.050
to 0.250 g (Figure 1). Subsequently, the effect of the temperature in the reaction was also studied.
When the reaction was conducted at 130 ◦C, a total conversion of phenol around 43% was obtained,
◦
which is twice the◦conversion reached at 100 C (see Figure 1, 21.5%). A further increase of the
temperature at 160 C gave a conversion of 54%. However, it was accompanied with a lower selectivity,
giving rise to the formation of a high number of byproducts. Accordingly, for further experiments,
the reaction temperature was set up at 130 ◦C.
◦
At the same microwave conditions (130 C, 0.250 g Amberlyst-15, 20 min), the Pechmann reaction
was performed under conventional thermal heating. After 20 min, the phenol conversion was not
higher than 18%. This result confirms the potential of microwave irradiation in this type of reaction as
an alternative to conventional heating methods.

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25
20
15
10
5
0
0
50
100
150
200
250
Catalyst mass (mg)
Figure 1. Effect of catal◦yst loading on the yield of 4-methylcoumarin: reaction time, 20 min;
reaction temperature, 100 C; and phenol/ethyl acetoacetate, molar ratio 1:1.
The catalytic performance of Amberlyst-15 was compared with those of H-β and TS-OS-SO3H
(Table 2). After a contact time of 20 min, 4-methylcoumarin was obtained in yields of 13% and 10%,
respectively. Again, the highest conversion was obtained over the polysulfonated resine due to its
highest amount of acid centers. In this case, the 4-methylcoumarin yield over H-β was similar to the
obtained over TS-OS-SO3H material, which indicated the better diffusion of the phenol, a mono-hydric
phenol, through the pores of the zeolite.
Table 2. Condensation reaction of phenol with ethyl acetoacetate with different heterogeneous catalysts. 1
Catalyst
Yield (%)
Amberlyst-15
H-β
TS-OS-SO3H
43
13
10
1 Reaction conditions: Molar ratio (phenol/ethyl acetoacetate) = 1:1, catalyst amount = 0.250 g, temperature = 130 ◦C,
reaction time = 20 min.
2.2. Reaction Mechanism
The plausible reaction mechanism for the Pechmann reaction of phenol with ethyl acetoacetate
was elucidated based on HPLC-MS analysis. The presence of 4-methylcoumarin and its intermediates
in the reaction mixture was confirmed by HPLC-MS measurements. The reaction pathway follows
the mechanism proposed by Robertson et al. [40] as illustrated in Scheme 3. Ethyl acetoacetate is
chemisorbed on the acid sites of the catalyst. The cation, thus formed, is a good electrophile and reacts
with phenol to generate a first intermediate I. The subsequent readsorption of the intermediate on the
acid site of the catalyst yields the second intermediate II with m/z = 225.10. Then, an intra-molecular
transesterification reaction results in ring closing, giving rise to the third intermediate III with
m/z = 149. Finally, its dehydration produces the final product, 4-methylcoumarin.

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Scheme 3. A plausible mechanism for the Pechmann condensation of phenol and ethyl acetoacetate
over acid catalysts.
3. Materials and Methods
3.1. Chemicals
Ethyl acetoacetate (
≥
99%), resorcinol (
≥
99%), phenol (
≥
99%), dodecane (
≥
99.8%) and
Amberlyst-15 were purchased from Sigma-Aldrich (St. Louis, MO, USA). Absolute ethanol
was provided by Panreac (Barcelona, Spain). The NH4-
β (Si/Al = 12.5 and Si/Al = 75) was
purchased from Zeolyst International company (Kansas, KS, USA). It was calcined at 600 ◦C
◦
(at a rate of 1 C/min) for 3 h to obtain the protonic form (H-
β). TEOS (tetraethyl orthosilicate),
BTEPTS (bis[3-(triethoxysilyl)propyl]-tetrasulfide) and Brij-76 (i.e., polyoxyethylene(10)stearyl alcohol)
were purchased from Aldrich.
3.2. Synthesis of Sulfonic Acid Functionalized Hybrid Silica (TS-OS-SO3H)
Sulfonic acid functionalized hybrid silica (TS-OS-SO3H) was synthesized according to our
previous method by using TEOS and BTEPTS as the silica and organosilica precursors [41]. A molar
ratio of the precursors of 75:25 was added to the synthesis mixture containing Brij 76 (6 g), HCl (19.6 mL)
and H2O (279 mL). The solution was stirred for 24 h at 50 ◦C, and, then, the suspension was aged at
90 ◦C for 24 h under static conditions. The resulting solid was recovered by filtration and dried in the
air. The surfactant was removed by successive extraction processes by heating the material at reflux
in a HCl solution (1 mL of 37% HCl and 50 mL of ethanol, per gram of solid) for 12 h. To oxidize the
tetrasulfide moieties to sulfonic acid groups, 0.3 g of material was stirred with 10 mL H2O2 (30%) at
50 ◦C for 3 h. Later, the solid was washed with 25 mL of 1.2 M H2SO4 and, then, washed with water
until a neutral pH was obtained. Finally, the solid was dried at 100 ◦C under vacuum.

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3.3. Microwave Assisted Solvent-Free Synthesis of Coumarin Derivatives
Solvent-free synthesis of coumarin derivaties was carried out by using microwave irradiation
(1000 W) in a FlexiWave Milestone Lab Microwave (Milestone Srl, Sorisol (BG), Italy) A 50 mL
microwave reaction tube equipped with a magnetic stirring bar (stirring capacity was set to 80%)
was charged with a mixture of resorcinol or phenol (10 mmol), ethyl acetoacetate (10 mmol) and
0.250 g of heterogeneous catalyst. The reaction mixture was kept in a microwave sealed tube at
130 ◦C for 20 min. The progress of the reaction was monitored by thin layer chromatography (TLC).
The resulting mixture was cooled to room temperature, treated with absolute ethanol and then filtered
to recover the catalyst. The reaction sample was analyzed by GC-MS using dodecane as an internal
standard. After evaporation of the solvent in a rotary evaporator, the crude solid was recrystallized in
aqueous ethanol to give the desired coumarin. Melting points were recorded on Stuart Electrothermal
Capillary melting point apparatus and are uncorrected. Pure products: 7-Hydroxy-4-methyl coumarin
(white solid, m.p. = 184.5 ◦C), 4-methyl coumarin (yellow solid; m.p. = 84 ◦C).
4. Conclusions
In summary, we have optimized the synthesis of 7-hydroxy-4-methylcoumarin and
4-methylcoumarin by Pechman reaction of resorcinol and phenol with ethyl acetoacetate by using
heterogenous acid solid catalysts under solvent-free microwave irradiation. The catalytic performance
of Amberlyst-15, zeolite-β and sulfonic acid functionalized hybrid silica, with different acidity and
surface properties, was evaluated. Among them, Amberlyst-15 showed much higher activity due to its
high density of acid centers.
Acknowledgments: S.B. acknowledges the support of Rocío Otero from Nanochemistry and Fine Chemistry
Research Institure (IUIQFN) for microwave experiments. J.A.G. acknowledges the collaboration fellowship
(2016-2017) from Ministry of Education, Culture and Sport (MECD). D.E.; M.I.L.; C.J.S. and F.J.R.S. gratefully
acknowledge the financial support from Ramon Areces Foundation, Andalusian Regional Government
(FQM-346 group), Spanish Ministry of Economy and Competitiveness (Project MAT2013-44463-R) and
Feder Funds.
Author Contributions: S.B., D.E. and F.J.R.-S. designed the experiments; J.A.-G and M.I.L. contributed to the
synthesis and data collection. C.J.-S. and M.T. contributed reagents/materials and analysis tools. All authors
contributed to writing the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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