Sonochemical synthesis of chromenes catalyzed by L-phenyl alanine-attached nano-Fe3O4@SiO2

ABSTRACT An efficient multi-component synthesis of 10,10-dimethyl-7-(phenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-diones is described by a one-pot condensation reaction of aldehydes, dimedone and 4-hydroxycoumarin using L-phenyl alanine tethered to nano-Fe3O4@SiO2 under ultrasonic irradiation. The catalyst has been characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDX), thermal gravimetric analysis (TGA) and vibrating-sample magnetometer (VSM). Atom economy, wide range of products, high catalytic activity, excellent yields in short reaction times, reusability of the catalyst and low catalyst loading are some of the important features of this protocol. GRAPHICAL ABSTRACT


Introduction
Ultrasound irradiation has been employed to accelerate a number of practicable reactions through the formation, growth, and implosive collapse of bubbles (1)(2)(3). Compounds with chromene structure are important substructures for both medicinal and synthetic organic chemists (4). Chromenes have received much attention due to their potency and wide spectrum of biological activities such as antimicrobial (5), antioxidant (6), antimalarial (7), antibacterial (8), and anticancer (9). Therefore, the development of facile, efficient, flexible and useful methods for the synthesis of chromenes is still favorable (10). Indeed, the synthesis of chromenes through multicomponent reactions (MCRs) has attracted much attention due to excellent synthetic efficiency, experimental simplicity, inherent atom economy and their ability to create molecular complexity starting from simple substrates (11,12). The core/shell Fe 3 O 4 nanoparticles are easily prepared and have been widely studied due to their unique physical properties. The core/shell Fe 3 O 4 nanoparticles can be recycled from the medium of reaction by external magnetic field (13,14). The surface of MNPs can be functionalized simply through suitable surface modifications to provide the attachment of a variety of favorable functionalities (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Therefor the modified magnetic nanoparticles with all these features are used for varied organic reactions under ultrasonic irradiations (25,26). The ultrasound approach offers several advantages such as higher yields, enhanced organic reaction rates, milder reaction conditions, and waste minimization compared with traditional methods and saving money and energy. Compared to conventional heating which provides thermal energy in the macro system, ultrasound irradiation is able to activate many organic reactions by providing the activation energy in micro environment (27)(28)(29)(30)(31)(32). Herein we report an efficient method for synthesize of L-phenyl alanine-supported Fe 3 O 4 @SiO 2 core/shell MNPs as an efficient catalyst for the preparation of 10,10-dimethyl-7-(phenyl)-10,11dihydrochromeno[4,3-b]chromene-6,8(7H,9H )-diones by one-pot condensation of aldehydes, dimedone and 4hydroxy coumarin under ultrasonic irradiation (Scheme 1).

Materials
All commercially available reagents were used without further purification and purchased from the Merck Chemical Company in high purity. The used solvents were purified by standard procedure.

Apparatus
Nanostructures were characterized using a Holland Philips Xpert X-ray powder diffraction (XRD) diffractometer (Cu K, radiation, λ = 0.154056 nm), at a scanning speed of 2°/min from 10°to 100°(2θ). Scanning electron microscope (SEM) of nanoparticles was performed on a Model FESEM. The magnetic properties of nanoparticles have been measured by a vibrating sample magnetometer (VSMF, PPMS-9 T) at 300 K Danesh Pajoh magnetic co. in Science and Technology Park, University of Kashan, Kashan Iran.
General procedure for the preparation of Fe 3 O 4 @SiO 2 -L-phenyl alanine nanocatalyst Nano-Fe 3 O 4 @SiO 2 -L-phenyl alanine were prepared as following; at first, nano-Fe 3 O 4 @SiO 2 microspheres (1 g) was dispersed in ethanol (30 mL) and a solution of 24 mL of sodium oleate in a 200 mL three-necked flask were vigorously stirred under an inlet of nitrogen, then mixture was kept under ultrasonic irradiation 90 W for 30 min. The Lphenyl alanine (0.6 gr) was then added to the suspension under ultrasonic irradiation for 30 min and nitrogen protection for 1 h. MNPs were separated by an external magnet and washed with water and ethanol and dried in an oven at 50°C for 9 h.

Characterization of compounds
10,10-Dimethyl-7-(4-methylphenyl)-10,11-dihydrochromeno [4,3-b] Table 1. The results show that the reaction was carried out efficiently in the presence of nano-Fe 3 O 4-@SiO 2 -L-phenyl alanine. The highest yield was obtained by 0.05 g of nano-Fe 3 O 4 @SiO 2 -L-phenyl alanine nanoparticle under ultrasonic irradiation with the power of 40W in ethanol. When the reaction was carried out under reflux conditions, it gave low yields of products and took longer reaction times, while the same reaction was carried out under ultrasonic irradiation to give good yields of products in short reaction times. The probable explanation for the positive association of irradiation is that the ultrasonic irradiation could increase the number of active cavitation bubbles and the size of the individual bubbles, both of which are expected to result in higher maximum collapse temperature and accelerated respective reaction.

Results and discussion
We also applied Fe 3 O 4 @SiO 2 -L-phenyl alaninenano catalyst in synthesis tetrahydrochromeno [4,3-b]chromene-6,8-dione derivatives from various aromatic aldehydes under similar condition as represented in Table 2. The results of this table indicate that the excellent yields were achieved in the presence of nano Fe 3 O 4-@SiO 2 -L-phenyl alanine (0.05 g). Electron-withdrawing substituents for aromatic aldehydes were given good to excellent yields of tetrahydrochromeno [4,3-b]chromene-6,8-diones (Table 2) To compare the efficiency of Nano-Fe 3 O 4 @SiO 2 -Lphenyl alanine with the reported catalysts for the sonosynthesis of 10,10-dimethyl-7-(phenyl)-10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives, we have tabulated the results in Table 3. As Table 3 indicates, Nano-Fe 3 O 4 @SiO 2 -L-phenyl alanine is superior with respect to the reported catalysts in terms of reaction time, yield and conditions. In addition, our catalyst was recyclable for five times. High catalytic activity and ease of recovery from the reaction mixture through magnetic field, and several reuse times without significant losses in performance are additional eco-friendly attributes of this catalytic system. TON and TOF of the nanocatalyst were provided. TON and TOF of the reactions clearly indicates that the method will be very useful for the synthesis of chromenes. (TON/TOF (min −1 ) = 9300/ 1550). EtOH (   A probable mechanism for the reaction using nano-Fe 3-O 4 @SiO 2 -L-phenyl alanine nanoparticle has been illustrated in Scheme 2. The synthesis of 10,10-dimethyl-7-(phenyl)-10,11-dihydrochromeno[4,3-b]chromene-6, 8 (7H, 9H)-dione derivatives involves a aldol condensation, Michael addition, cyclization and isomerization, respectively. These processes performed on the nano-Fe 3 O 4-@SiO 2 -L-phenyl alanine which has highly effective catalytic behavior in terms of its high surface area. The formation of product can be rationalized by initial aldol condensation reaction between an aldehyde 1 and dimedone 2; then, Michael addition reaction between α, β-unsaturated carbonyl (intermediate (I)) and 4-hydroxy coumarin gives intermediate (II) followed by cyclodehydration would give the desired 10,10-Dimethyl-7-(phenyl)-10,11dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives in the presence of nano-Fe 3 O 4 @SiO 2 -L-phenyl alanine (Scheme 2). The amino groups distributed on the surface of Fe 3 O 4 @SiO 2 activate the C=O groups for better reaction with nucleophiles through hydrogen bonding (40,41). Nanoparticles exhibit good catalytic activity due to their large surface area and active sites which are mainly responsible for their catalytic activity. As it obvious, obtained catalyst has a uniform and spherical morphology (see supporting information figure S3). These surface atoms behave as the centers where the chemical reactions could be catalytically activated. Nanoscale heterogeneous catalysts present higher surface areas, which are mainly responsible for their catalytic activity.
The reusability is one of the significant properties of this catalyst. The reusability of Fe 3 O 4 @SiO 2 -L-phenyl alanine was studied for the reaction of 4-nitrobenzaldehyde, dimedone and 4-hydroxycoumarin and it was found that product yields decreased to a small extent on each reuse (run 1, 96%; run 2, 95%; run 3, 95%; run 4, 93%; run 5, 93%). After completion of the reaction, the nanocatalyst was easily separated using an external magnet. The recovered magnetite nanoparticles were washed several times with acetone and then dried at room temperature ( Figure 1). Ideally, introducing neat processes and utilizing eco-friendly and green catalysts which can be simply recycled at the end of reactions has received significant attention in recent years.
To determine the extent of Fe leaching after the reactions, we have used the hot filtration test (42). For this aim, we have studied the model reaction between 4nitrobenzaldehyde, dimedone and 4-hydroxycoumarin under optimized condition. The reaction mixture was filtered after 50% conversion to remove the catalyst. Continuation of the reaction under the same conditions showed 52% conversion after 6 min. This result shows that the amount of leaching of the catalyst into the reaction mixture should be low and confirms that the catalyst acts heterogeneously in the reaction.
To determine the degree of leaching of the metal from the heterogeneous catalyst, the catalyst was removed by filtration and the Fe amount in reaction medium after each reaction cycle was measured through inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The analysis of the reaction mixture by the ICP technique showed that the leaching of Fe was negligible (The leaching of Fe in five continuous runs was found to be ≤0.08 ppm). We believe that, this is also the possible reason for the extreme stability of the nanocatalyst presented herein.