Three-component reactions of kojic acid : Efficient synthesis of Dihydropyrano [ 3 , 2-b ] chromenediones and aminopyranopyrans catalyzed with Nano-Bi 2 O 3-ZnO and Nano-ZnO

Article history: Received January 2, 2017 Received in revised form March 1, 2017 Accepted April 21, 2017 Available online April 22, 2017 Synthesis of pyrano-chromenes and pyrano-pyrans was developed by three-component reactions of kojic acid and aromatic aldehydes with dimethone and malononitrile, catalyzed with nano-Bi2O3-ZnO and nano-ZnO, respectively. Reactions proceeded smoothly and the corresponding heterocyclic products were obtained in good to high yields. Nano ZnO and nano Bi2O3-ZnO were prepared by sol-gel method and characterized by X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDX), Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. Supporting Bi3+ on ZnO nanoparticles as Bi2O3, is the main novelty of this work. The simple reaction procedure, easy separation of products, low catalyst loading, reusability of the catalyst are some advantageous of this protocol. © 2017 Growing Science Ltd. All rights reserved.


Introduction
Multi-component reactions (MCRs) have been attracted a lot of attention in organic and pharmaceutical chemistry because of the construction of biologically active compounds. 1Although, these reactions are complicated than stepwise reaction, they are fast, efficient and environmentally favorable methods.
Chromenes and pyrano-pyranes are important classes of fused oxygenated heterocycles 2 with a wide range of biological and therapeutic properties, such as antibacterial, 3 anti-cancer, 4 antianaphylactic, 5 and anticonvulsant activities. 6Also, they are extensively found in natural products, such as biscopyran, 7 Elatenyne, 8 Calyxin I, Calyxin J, and Epicalyxin J. 9 Therefore, the development of efficient and convenient methods for the synthesis of chromene and pyranopyran derivatives using a recyclable and environmentally benign catalyst is very necessary.Three-component reaction of kojic acid, aldehyde and 1,3-dicarbonyl compounds or malononitrile is one of the most important methodology for the synthesis of these heterocyclic systems.A various catalysts and conditions were reported for this reaction, including InCl3, 10 CAN, 11 Al2O3, 12 Bi(OTf)3, 13 CeCl3•7H2O/SiO2, 14 FeCl3-SiO2, 15 Fe3O4@SiO2, 16 ultrasonic irradiation, 17 imidazole, 18 piperidine, 19 Et3N, 20 and NH4VO3. 21Kojic acid and its derivatives have wide range of applications in cosmetic, 22 medicine, 23 food, 24 agriculture 25 and chemical industries. 26 the other hand, metal oxides play a crucial role in many areas of chemistry, physics and materials science. 279] Among them, bismuth and zinc oxides are as effective catalysts because of their low toxicity, ease of handling, low cost and relative insensitivity to air and moisture. 30n continuing our works on the heterocyclic chemistry, [31][32][33] we report herein a one pot three-component synthesis of chromenes and pyranopyarns from kojic acid catalyzed by nano-Bi 2 O 3 -ZnO and nano-ZnO, respectively.

Results and Discussion
ZnO nanoparticles were prepared using a polyethylene glycol (PEG) sol-gel method as reported by Amini et al., 34 by heating a solution of Zn(NO3)2 and PEG in EtOH until forming a viscous gel, followed by drying and calcination in air at 500 °C.Then, Bi2O3-ZnO nanoparticles were prepared by adding nano-ZnO to a solution of BiCl3 in MeOH for 24 h, and drying in air at room temperature.Obtained nano-ZnO and nano-Bi2O3-ZnO were characterized using FT-IR, SEM, XRD, EDX and TEM analysis.XRD pattern of the nano-ZnO shows peaks at the positions of 31.63°,34.31°, 36.11°,47.48°, 56.55°, 62.80°, 66.33°, 67.90° and 69.04°, which are in good agreement with reported data. 34In addition to peaks related to nano-ZnO, peaks at the positions of 32.78°, 33.47°, 37.86°, 44.77° was appeared in the XRD pattern of the nano-Bi2O3-ZnO, accounted to the existence of β-Bi2O3 35 in the composition of nanoparticles (Fig. 1.).Particle morphology and textural properties of nano-ZnO and nano-Bi2O3-ZnO catalysts were studied by SEM and TEM images, in which the nanoparticles of ZnO were appeared as regular geometric shapes such as cubic and rod like materials (Fig. 3a.).SEM images of Bi2O3-ZnO showed the similar shape with nano-ZnO with Puffy and wrinkled surface (Fig. 3b.).TEM images of Bi2O3-ZnO revealed that the existence of ZnO nanoparticles with very tiny particles of Bi2O3 on its surface (Fig. 3c,d.).Energy dispersive X-ray analysis was used for the elemental analysis of nanoparticles.EDX data of nano ZnO showed the weight percentage of 89.85% and 10.15% of Zn and O, respectively.EDX analysis of BiCl3-ZnO composite did not exhibit the Cl in the structure, where the Zn, Bi and O weight percentage were determined as 69.39%, 19.28% and 11.33%, respectively, indicating the formation of nanoparticles of Bi2O3 by hydrolysis of BiCl3 with water molecules on the surface of nano-ZnO in MeOH.
The catalytic activity of the prepared nano-Bi2O3-ZnO was investigated by reacting of dimethone and benzaldehyde with 1.1 equiv. of kojic acid in the presence of catalytic amount of nano-Bi2O3-ZnO in EtOH under reflux conditions for 6 h, leading to corresponding chromene 3a in 40% yield (Table 1, Entry 1).Increasing the reaction time did not improve the yield.In order to obtain the best reaction conditions, the reaction was carried out in different solvents under reflux conditions, such as water, MeCN, CH2Cl2 and solvent-free conditions (Entries 2-5).In water Knoevenagel product 4 was obtained as major product along with the desired product in very low yield.However, reaction in MeCN did not occur.In CH2Cl2, 23% of desired product 3a was obtained.Heating a mixture of kojic acid, dimethone and benzaldehyde in the presence of catalytic amount of nano-Bi2O3-ZnO at 100 °C under solvent-free conditions for 2 h, furnished the chromene 3a in 80% yield (Entry 5).By decreasing the reaction temperature (Entries 5-8), not only the reaction time was increased, but also the yield was decreased, as there is no product detected at room temperature after 8 h.When reaction was conducted at elevated temperature (110 °C), the product 3a was obtained in 66% along with formation of a mixture of nonisolable colored complex byproducts (Entry 9).In order to determine the optimum amount of catalyst, similar reaction was performed in the presence 0.01, 0.02, 0.03 and 0.05 g of nano-Bi2O3-ZnO catalyst, from which the 0.03 g of catalyst was selected for the best result (Entries 5, 11-13).In the absence of nano-Bi2O3-ZnO catalyst, reaction did not afford the desired product (Entry 10).When reaction was conducted using nano-ZnO, chromene 3a was obtained only in 20% isolated yield, with a complex mixture of byproducts, as monitored by TLC (Entry 14).To investigate the effect of Bi 3+ , reaction was also applied in the presence of BiCl3 (5 mol%), resulted in formation of octahydroxanthene 5 as major product, along with formation of desired product in low yield (Entry 15).Recoverability of the catalyst was studied by separation of catalyst by simple filtration, followed by washing with CH2Cl2 three times, and then drying at 50 °C under vacuum.The remaining catalyst reloaded with fresh reagents under the reaction conditions for four further runs, in which no considerable decrease in the yield was observed, demonstrating that nano-Bi2O3-ZnO can be reused as a catalyst (Entry 5).With optimum conditions in hand, nano-Bi2O3-ZnO catalyzed three component synthesis of chromene derivatives were investigated using various substituted benzaldehydes (Scheme 1).Reactions were carried out by heating a mixture of a substituted benzaldehyde, dimethone and 1.1 equiv. of kojic acid in the presence of nano-Bi2O3-ZnO (0.03 g, 2.8 mol% of Bi) at 100 °C for 2 h, to afford chromenes 3a-h in 75-84% yields.The results are summarized in Table 2.As shown in Table 2, not only electronwithdrawing substituted benzaldehydes, such as Cl and NO2 substituted benzaldehydes afforded corresponding desired products in high yields, but also electron donating substituted benzaldehydes, 4-Me and 4-MeO substituted benzaldehydes worked well under the reaction conditions.a Reactions were carried out under solvent-free conditions at 100 °C for 1-2 h.
The results encouraged us to investigate the synthesis of pyrano-pyran derivatives 7 via nano-Bi2O3-ZnO catalyzed three-component reaction between kojic acid, substituted benzaldehydes and malononitrile.By treatment of malononitrile with kojic acid and benzaldehyde in the presence of catalytic amount of nano-Bi2O3-ZnO at 100 °C for 5 h, reaction did not proceed smoothly and only 24% yield of product was obtained, along with a complex mixture of byproducts.So, the reaction was examined under different conditions, including various solvents, temperatures and using other catalysts such as BiCl3 and nano-ZnO.Conducting reaction with 0.03 g of nano-ZnO in refluxing EtOH resulted in formation of corresponding pyrano-pyran 7a in 94% yield, within 2 h of reaction time.Then, the scope of the reaction was investigated by reaction of variety of aromatic aldehydes, in which the corresponding pyrano-pyrans 7a-f were obtained in 81-95% yields (Scheme 2, and Table 3).A plausible reaction mechanism involves the nano-Bi2O3-ZnO induced enolization of dimethone via hydrogene bond or coordination to Bi atom (a), which attached to hydrogen bond activated aldehyde (b) to give intermediate I. Water removing from I led to knoevenagel intermediate II (c), which underwent conjugate addition with kojic acid, activated with hydrogen bond with Bi=O (d), to generate intermediate III.Intermediate III was converted to final product V by intramolecular cyclization to IV (e), followed by water removal (f).As shown in Scheme 3, the Zn-O-Bi-O bonds, produced as hydrat form of Bi2O3 on nano-ZnO, and hydrogen bonds formed between starting components and also in-situ generated intermeditaes, played an important role in catalytic activity of Bi2O3-ZnO, for this type of transformation.As mentioned above (Table 1, entry 14), the Bi2O3 is essential for the reaction of dimethone, benzaldehyde and dimethone.Due to the high reactivity of malononitrile, in the presence of Bi2O3-ZnO the reaction is uncontrollable, leading to a complex mixture.While nano-ZnO in the absence of Bi2O3 exhibited acceptable catalytic acitivity.

Scheme 2. Nano-ZnO-catalyzed synthesis of pyranopyrans
The comparison of the catalytic activity of nano-Bi2O3-ZnO in the three-component reaction of aromatic aldehydes, kojic acid and dimethone with some of the reported catalytic systems was summarized in Table 4. However the reaction temperatures and yields of the products are comparable, but due to the low mol% of catalyst loading, nano-Bi2O3-ZnO is efficient and effective catalytic system.In the case of cyclocondensation of aromatic aldehydes, kojic acid and malononitrile using nano-ZnO, reaction temperature and times, along with the yields of the corresponding products are also comparable with reported ones.

Conclusions
In summary, ZnO and Bi2O3-ZnO nanoparticles were synthesized and characterized using FT-IR, XRD, SEM, EDX and TEM techniques.This the first report on the preparation of Bi2O3 supported on ZnO nanoparticles by simple hydrolyzing BiCl3 in the presence of ZnO nanoparticles.Threecomponent reaction of kojic acid, aldehyde and dimethone was catalyzed with nano-Bi2O3-ZnO and pyranochromenes were obtained in good to high yields.In the case of malononitrile, reaction was not progressed in the presence of nano-Bi2O3-ZnO, but reaction catalyzed with nano-ZnO and pyranopyranes were produced in high yields.The recoverability of the catalyst was studied, in which the catalyst was reused in four further runs without loss of efficiency.

Material and Methods
All chemicals were purchased from Merck and Sigma-Aldrich and used without any further purification.Solvents were used as received from commercial suppliers.NMR spectra were recorded using a Bruker instrument at 500 MHz and 125 MHz for proton and carbon nuclei, respectively, in CDCl3 or DMSO-d6.FT-IR spectra were measured as a KBr disc using a Win-Bomem, version 3.04 Galatic Industries Corperation, spectrometer.X-ray diffraction (XRD) patterns were measured using a Bruker D8 Advance with CuK (α) radiation (λ = 0.15406 nm) in the range 4° < 2θ < 70°.Scanning electron microscope (SEM) images and EDX analysis were obtained using a VWGA3 TESCAN (20.0 KV) microscope.Transmission electron microscopy (TEM) images were recorded using a Philips CM120 microscope.

Synthesis of nano-ZnO
Zn(NO3)2.6H2O(1.0 g) was dissolved in the solution of PEG (1.5 g) and ethanol (20 ml) with constant stirring at 150 °C until forming a viscous gel.After that the obtained viscous gel was dried at 350 °C for 30 min, and then the dried precursors were ground into powder and calcined in air at 500 °C for 6 h, to produce ZnO nanoparticles.

Synthesis of nano-Bi2O3-ZnO
Nano-ZnO (1.46 g) was added to a solution of BiCl3 (0.63 g) in MeOH (10 ml) and stirred at room temperature for 24 h.Then, the solvent was evaporated and the obtained solid material was dried at room temperature in air, overnight.

General procedure for the synthesis of pyrano-chromenes
To a mixture of kojic acid (1.1 mmol), dimethone (1 mmol) and an aldehyde (1 mmol) was added nano-Bi2O3-ZnO (0.03 g) and stirred at 100 °C under solvent free condition for 1-2 h.After completion of the reaction (monitored by TLC), CH2Cl2 was added and catalyst was removed by filtration.Solvent was evaporated and crude products were purified by flash chromatography on silica gel using hexaneacetone (7:3) as an eluent.Obtained products were characterized by FT-IR, NMR and melting points in comparison with authentic samples.

General procedure for the synthesis of pyrano-pyrans
Nano-ZnO (0.03 g) was added to a solution of kojic acid (0.5 mmol), malononitrile (0.5 mmol) and aldehyde (0.5 mmol) in EtOH (10 mL) and refluxed for 1-2 h.After completion of the reaction (monitored by TLC), catalyst was separated by filtration, and the reaction mixture was cooled and desired product recrystallized from the solution.Obtained products were characterized by FT-IR, NMR and melting points in comparison with authentic samples.

Table 1 .
Optimization of the reaction conditions a

Table 3 .
Nano-ZnO catalyzed synthesis of aminopyrano-pyrans a a Reactions were carried out in refluxing EtOH for 1-2 h.

Table 4 .
Comparison of the catalytic activity of nano-Bi2O3-ZnO with other catalysts.
a Three component reaction between 4-chlorobenzaldehyde, dimethone and kojic acid under solvent free condition.b Three component reaction between benzaldehyde, malononitrile and kojic acid.