A Fast , Highly Efficient , and Green Protocol for Synthesis of Biscoumarins Catalyzed by Silica Sulfuric Acid Nanoparticles as a Reusable Catalyst

A variety of biological activities are associated with coumarins and biscoumarins, for example, anticoagulants and antianthelmintic and antifungal activities [1–3]. Furthermore, these compounds can be complexed with rare earth metals as anti-HIV agents [4]. The synthesis of biscoumarins has been reported in the presence of piperidine [5],molecular iodine [6], tetrabutylammonium bromide [7], [bmim]BF 4 [8], sodium dodecyl sulfate [9], SO 3 H-functionalized ionic liquid [10], and [MIM(CH 2 ) 4 SO 3 H][HSO 4 ] [11]. In this paper, we report a simple and efficient method for synthesis of biscoumarin derivatives using different aromatic aldehydes and phenylglyoxals and 4-hydroxycoumarin in the presence of silica sulfuric acid nanoparticles under reflux in ethanol. The catalyst is recyclable with reproducible results without any loss of its activity. The morphology of the silica sulfuric acid nanoparticles was observed using a scanning electron microscope (SEM).

In this paper, we report a simple and efficient method for synthesis of biscoumarin derivatives using different aromatic aldehydes and phenylglyoxals and 4-hydroxycoumarin in the presence of silica sulfuric acid nanoparticles under reflux in ethanol.The catalyst is recyclable with reproducible results without any loss of its activity.The morphology of the silica sulfuric acid nanoparticles was observed using a scanning electron microscope (SEM).

Experimental
2.1.General.IR spectra were recorded on a Shimadzu IR-470 spectrometer in KBr discs.The NMR spectra were obtained on a Bruker Avance DRX-500 FT spectrometer ( 1 H NMR at 500 Hz, 13 C NMR at 125 Hz) using CDCl 3 as solvent with TMS as internal standard.Melting points were determined with an Electrothermal 9100 apparatus.Elemental analyses were performed using a Costech ECS 4010 CHNS-O analyzer at Analytical Laboratory of Science and Researches Unit of Islamic Azad University.The morphology of the catalyst was observed using an SEM model VEGA//TESCAN with an accelerating voltage of 15 kV.The chemicals used in this work were purchased from Sigma Aldrich and Fluka (Buchs, Switzerland) and were used without further purification.

Synthesis of Silica Sulfuric Acid
Nanoparticles.The reagent was prepared by combination of chlorosulfonic acid (23.3 g) drop by drop over 10 min via a syringe to nanosilica gel powder (60 g) in a 100 mL flask at 0 ∘ C. The reaction mixture was then stirred, and then after 30 min, the white powder was separated.The dimensions of nanoparticles were observed with SEM (Figure 1).The size of particles is between 28 and 32 nm.

General Procedure for the Synthesis of Biscoumarin.
A mixture of 4-hydroxycoumarin (2 mmol), aromatic aldehyde or arylglyoxal (1 mmol), SiO 2 -OSO 3 H NPs (0.003 g), and EtOH (5 mL) was placed in a round bottom flask.The materials were mixed and refluxed for 20 min.The progress of the reaction was followed by TLC (n-hexane:ethylacetate).After completion of the reaction, the mixture was filtered to remove the catalyst.By evaporation of the solvent, the crude product was recrystallized from hot ethanol to obtain the pure compound.

Results and Discussion
In continuation of our investigations of the application of solid acids in organic synthesis [12][13][14][15][16], we have investigated the synthesis of biscoumarin derivatives by condensation of a 4-hydroxycoumarin 1 and an aromatic aldehyde 2 or phenylglyoxals 3 in the presence of 0.003 g SiO 2 -OSO 3 H NPs catalyst.
The stable silica gel nanoparticles are easily prepared [17] and used for preparation of catalyst (SiO 2 -OSO 3 H NPs).
To optimize the reaction conditions, the reaction of benzaldehyde and 4-hydroxycoumarin was used as a model reaction.Initially, the catalytic activity of SiO 2 -OSO 3 H NPs has been compared with other catalysts, according to the obtained data, and this catalyst afforded good yields; however, it has limitations of long reaction time, harsh reaction conditions, and often expensive catalysts (Table 1, entry 1-6).In order to determine the optimum quantity of SiO 2 -OSO 3 H NPs, model reaction was carried out at reflux in ethanol condition (Table 1, entry 7-9).SiO 2 -OSO 3 H NPs (0.003 g) gave an excellent yield in 20 min (Table 1, entry 8).The previous reaction was also examined in various solvents.The best results were obtained when EtOH was used as a solvent at reflux (Table 1, entry 8).An interesting feature of this method is that the reagent can be regenerated at the end of the reaction and can be used several times without losing its activity.To recover the catalyst, after completion of the reaction, the mixture was filtered, and catalyst was washed with CHCl 3 , and then the solid residue dries.This process was repeated for two cycles, and the yield of product 4a did not change significantly (Table 1, entry 12, 13).To study the scope of the reaction, a series of aromatic aldehydes or phenylglyoxals and 4-hydroxycoumarin catalysed by SiO 2 -OSO 3 H NPs were examined (Scheme 1).The results are shown in Table 2.In all cases, aromatic aldehyde or phenylglyoxals substituted with either electrondonating or electron-withdrawing groups underwent the reaction smoothly and gave products in excellent yields.
The compounds 4a-l were characterised by their 1 H-NMR and IR spectroscopies and elemental analyses.Spectral data were compared with the literature data [5,9,11].
Compounds 4m, n and 5a-c were new, and their structures were deduced by elemental and spectral analysis.The 1 H-NMR spectrum of compound 5a exhibited proton of methine at 6.4 ppm, and OH proton is observed at 11.3 ppm which disappears after addition of some D 2 O to the CDCl 3 solution of 5a.There are observed multiplets between 7.34 and 8.29 ppm which are related to aromatic protons.The 13 C-NMR spectrum of compound 5a showed 15 signals in agreement with the proposed structure.The IR spectrum of compound 5a also supported the suggested structure.

Conclusion
In summary, we have reported an easy and efficient protocol for the synthesis of biscoumarins in the easily accessible SiO 2 -OSO 3 H nanoparticles.The method offers marked improvement with its operational simplicity and short reaction time and affords excellent yield.The solid phase acidic catalyst was reusable for a number of times without appreciable loss of activity.The present method does not involve any hazardous organic solvent.Therefore, this procedure could be classified as green chemistry.

Scheme 1 :
Scheme 1: Synthesis of biscoumarins by condensation of 4-hydroxycoumarin with an aromatic aldehyde or phenylglyoxals using SiO 2 -OSO 3 H NPs as catalyst.

Table 1 :
Synthesis of 4a under various conditions.
a Isolated yield, b tetrabutylammonium bromide, and c sodium dodecyl sulfate.
a Isolated yield.