Ultrasound-assisted synthesis of kojic acid-1,2,3-triazole based dihydropyrano[3,2-b]pyran derivatives using Fe3O4@CQD@CuI as a novel nanomagnetic catalyst

The magnetic nanoparticles coated with carbon quantum dot and copper (I) iodide (Fe3O4@CQD@CuI) were used as eco-friendly heterogeneous Lewis / Brønsted acid sites and Cu (I) nanocatalysts. In the first step, it was applied in the synthesis of kojic acid-based dihydropyrano[3,2-b]pyran derivatives in a three-component reaction and in the second step, as a recyclable catalyst for the synthesis of kojic acid-1,2,3-triazole based dihydropyrano[3,2-b]pyran derivatives in the CuI-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The catalyst was characterized fully by using the different techniques including fourier transform infrared spectroscopy (FT-IR), elemental mapping analysis, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), X-ray spectroscopy (EDX), transmission electron microscopy (TEM), thermal gravimetric (TG) and value-stream mapping (VSM) methods. The final synthesized derivatives were identified by 1H- and 13C-NMR spectroscopy.

www.nature.com/scientificreports/ presence of each ring in the skeleton is a reason for the occurrence of biological and medicinal properties in the structure 38,39 . In 2001, Club, Finn, and Sharpless introduced click reaction as a group of chemical reactions in the synthesis of heterocycles that have potential advantages over traditional reactions such as ease of execution, easy separation, and inexpensive solvents. The most used "click" reaction that can fulfil these conditions is by far the CuI-catalyzed azide/alkyne cycloaddition (CuAAC) [40][41][42][43][44][45][46][47][48] .
In this paper, we successfully developed a new method for the synthesis of heterocyclic polycyclic compounds using a new heterogeneous nanocatalyst based on CQDs as a nano-catalyst under ultrasonic condition. The novel catalyst Fe 3 O 4 @CQD@CuI was used to synthesize kojic acid-based dihydropyrano [3,2-b]pyran derivatives in a multicomponent reaction of kojic acid, malononitrile, and various aldehydes and kojic acid-triazole based dihydropyrano-pyran derivatives via a click reaction, respectively. Subsequently, the newer triazole compounds were synthesized using benzyl halide derivatives and sodium azide (Fig. 1).

Synthesis of Fe 3 O 4 nanoparticles.
In a 250 mL round-bottomed flask, 10 mmol FeCl 3 ·6H 2 O and 5 mmol FeCl 2 ·4H 2 O were well dissolved in 100 mL distilled water and was stirred. Then 10 mL NH 4 OH drop by drop was added to the mixture until the pH reached to 11. Then, the mixture was stirred under reflux condition for 1 h under N 2 atmosphere. Finally, iron oxide nanoparticles were separated with an external magnet and washed several times with distilled water (Fig. 2) 49 .
Synthesis of CQD with glucose. In a 100 mL round-bottomed flask, 5 g of glucose was added to 10 cc of oil, a mixture of oleic acid (65%), linoleic acid (30%) and stearic acid (5%), which had already been heated to 250 °C. Half-burning of glucose in a mixture of the above acids led to the formation of carbon quantum dot. With the browning of glucose, the burning of glucose stopped and after cooling the mixture, by adding 30 mL of water and 30 mL of diethyl ether, carbon dot was separated through the aqueous phase ( Fig. 2) 13 .

Synthesis of Fe 3 O 4 @CQD nanocomposite.
Iron oxide nanoparticles Fe 3 O 4 (1 g) was dispersed in 50 mL of water for 15 min with ultrasonic, then 0.05 g of carbon dot was added and stirred well for 24 h at room temperature. Finally, it was easily separated by an external magnetic field and washed twice with distilled water (Fig. 2) 14 .

Synthesis of Fe 3 O 4 @CQD@CuI.
Loading of copper iodide on the Fe 3 O 4 @CQD was done by dispersing 1 g of Fe 3 O 4 @CQD in 50 mL of methanol, on the other hand 1 mmol of copper iodide was sonicated in 5 mL of methanol and then two solutions were mixed and stirred for 12 h under reflux condition. Finally, it was separated with a super magnet and washed with methanol (3 × 5) (Fig. 2).
General procedure for the synthesis of kojic acid based dihydropyrano[3,2-b]pyran-derivatives using Fe 3 O 4 @CQD@CuI. A mixture of kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4one) (1 mmol, 0.142 g), aromatic aldehydes (1 mmol), malononitrile (1.2 mmol, 0.066 g) and nano catalyst Fe 3 O 4 @CQD@CuI (5 mg) in a round-bottomed flask were sonicated in an ultrasonic bath in mixture of ethanol and H 2 O (2:1) as solvent. The progress of the reaction was monitored using TLC (n-hexane:ethyl acetate, 1:3). After the reaction was completed, the insoluble catalyst was easily separated by an external magnet bar. After evaporation of solvent, the precipitate was collected and recrystallized with ethanol (5 mL) to afford the pure product (  www.nature.com/scientificreports/ 0.078 g), benzyl chloride derivatives (1.2 mmol) and nano catalyst Fe 3 O 4 @CQD@CuI (0.01 g) were sonicated in 5 mL water. The progress of the reaction was monitored using TLC (ethyl acetate:MeOH, 8:1). After the reaction was completed, 5 mL ethyl acetate was added and the catalyst was easily separated by an external magnet bar. Then, the product was separated through the organic phase. The residue was purified by plate chromatography (ethyl acetate: methanol, 95:5) to give the desired products ( Fig. 1). The analytic results (melting points, FT-IR, NMR) are provided in the supporting file (Supplementary Information).

Result and discussion
The structure of Fe 3 O 4 @CQD@CuI as a nano magnetic catalyst coated with carbon quantum dot containing the hydroxyl and carboxyl groups on its surface with copper iodide, was studied and fully characterized by FT-IR, elemental mapping analysis, the scanning electron microscopy (SEM), X-ray spectroscopy (EDX), transmission electron microscopy (TEM), Thermal gravimetric (TG-DTG), X-ray photoelectron spectroscopy (XPS) and value-stream mapping (VSM) methods. The characterization of Fe 3 O 4 @CQD and Fe 3 O 4 @CQD@CuI were confirmed and compared by FT-IR spectroscopy in Fig. 3. The broad peak that appeared at 3000-3500 cm −1 was related to OH and CO 2 H groups of CQD. Also, the absorption bands appeared at 1642 cm −1 and 1441 cm −1 Which are related to stretching modes C=O and C=C bonds, respectively. The peak in the region of 1000 to 1200 cm −1 is related to the C-O stretching modes of CQD. The aromatic ring in the carbon dot skeleton was observed. Furthermore, the peak of Fe-O of Fe 3 O 4 appeared at 642 cm −1 .
Using SEM, the morphology of the surface and particle size of Fe 3 O 4 @CQD@CuI were investigated. In Fig. 4, SEM images revealed that the shape of particles was spherical and dimensions were in a nanoscale size (approximately 26-55 nm based on images of SEM). TEM images (Fig. 5A,B) showed that the morphology of Fe 3 O 4 nanoparticles was also spherical and the average size was less than 20 nm. TEM images also indicated numerous small particles (CQDs) with sizes about fewer than 10 nm surrounding Fe 3  www.nature.com/scientificreports/ EDX and elemental mapping analysis confirmed the presence of iron (Fe), carbon (C), oxygen (O), copper (Cu) and iodine (I) components in the catalyst based on Fig. 6. The results of elemental mapping analysis also revealed that the elements had a uniform distribution in the catalyst structure.
The pattern of thermal gravimetric (TGA-DTG) curve of Fe 3 O 4 @CQD@CuI as shown in Fig. 7, revealed three stages of weight loss for Fe 3 O 4 @CQD@CuI up to 600 °C. The first weight loss (1-2%) which observed between 25 and 100 °C was related to the removal of moisture from the catalyst structure. The second weight loss (5-6%) appeared at 400 °C, which was attributed to the release of CO 2 groups due to C-C bond breaking of the aromatic ring and the carboxylic acid groups. The final stage of weight loss (10-12%) at 600 °C was assigned to the decomposition of the carbon quantum dot coated on the Fe 3 O 4 . In addition, The Differential Thermogravimetric (DTG) curve shows endothermic peaks in this region which confirms the successful chemical adsorption of organic complex layers via chemical bonding on the support. XPS analysis is a powerful surface sensitive technique that has been used to confirm the chemical composition, purity, and oxidation states of element. The C 1s (carbon 1s) peak at 284.60 eV was used as a reference for the calibration of all binding energies. Figure 8a shows the wide scan spectrum XPS (survey spectrum) of the  (Fig. 8c) 50 . Figure 8d shows the spectrum of the nucleus of a copper atom on the surface of the catalyst. The peak at 932.37 eV and 951.61 eV are related to Cu 2p 3/2 and Cu 2p 1/2 , respectively. Also, the appearance of two satellite peaks at 95.53 eV and 942.43 eV confirms the existence of Cu-O bonds [51][52][53] . The XPS results of Cu 2p indicate that copper ions exist   An attempt was made to investigate magnetic measurements of Fe 3 O 4 @CQD@CuI at the room temperature using vibrating sample magnetometer (VSM). As shown in Fig. 9, based on magnetization curves, the saturation of the obtained catalyst dropped to 58.11 emu g −1 .

Application of Fe 3 O 4 @CQD@CuI as magnetic nanoparticle (MNP) catalyst in the synthesis of kojic acid based dihydropyrano[3,2-b]pyran and new kojic acid-triazole hybrid based dihydropyrano[3,2-b]pyran derivatives. After the synthesis and fully characterization of Fe 3 O 4 @
CQD@CuI, Beginning to investigate its catalytic activity, it was used as a MNP catalyst for the synthesis of kojic acid based dihydropyrano[3,2-b]pyran derivatives in a multi component reaction via a condensation reaction of suitable starting materials. In the following, the new triazole compounds were synthesized via the click reaction using kojic acid based dihydropyrano[3,2-b]pyran derivatives having an acetylene group in the presence of MNP catalysts Fe 3 O 4 @CQD@CuI.
In order to optimize the reaction condition, the three-component reaction were performed between kojic acid (1 mmol, 0.142 g), malononitrile (1.1 mmol, 0.072 g) and benzaldehyde (1 mmol, 0.106 g) to synthesis kojic acid based dihydropyrano[3,2-b]pyran derivatives under various conditions including different temperatures, reflux and ultrasonic in water, acetonitrile, ethanol, ethyl acetate and n-hexane (5 mL) as solvents in the presence a catalytic amount of Fe 3 O 4 @CQD@CuI. Based on the results shown in Table 1, a mixture of water and ethanol (1:2) as solvent and ultrasonic condition at 50 °C was the best condition of reaction for the synthesis of kojic acid based dihydropyrano[3,2-b]pyrans derivatives (Table 1, entry 9). Any change did not appearance    www.nature.com/scientificreports/ After determining the best reaction conditions for synthesis of dihydropyrano [3,2-b]pyrans, a wide range of aromatic aldehydes having the electron-donating and electron-withdrawing groups were synthesized (Fig. 10). As specified in Table 2, the aldehydes with electron-withdrawing groups compared to electron-donating groups resulted in higher efficiencies in this reaction.
This observation can be excused on the basis of the acceptable mechanism suggested for the synthesis of kojic acid based dihydropyrano[3,2-b]pyrans using Fe 3 O 4 @CQD@CuI catalyst as shown in Fig. 11. According to the reaction pathway, aldehyde is initially activated by the acidic and hydroxyl sites of the catalyst, then reacts with The recovery and reusing capability of the catalyst in a model reaction in the synthesis of kojic acid based dihydropyrano-pyran derivatives was investigated. Kojic acid (1 mmol, 0.142 g), malononitrile (1.1 mmol, 0.072 g) and benzaldehyde (1 mmol, 0.106 g) were used for this purpose. The results showed that the MNP catalyst of Fe 3 O 4 @CQD@CuI could be recovered and reused up to 5 times without any noticeable loss of catalytic activity (Fig. 12).
After the high efficiency revelation of this catalyst in the synthesis of kojic acid based dihydropyrano[3,2b]pyrans different derivatives, a new class of kojic acid-triazole hybrids were investigated using acetylene of dihydropyrano [3,2-b]pyrans derivatives. In order to synthesize triazole derivatives, the reaction between 2-amino-6-(hydroxymethyl)-8-oxo-4-(4-(prop-2-yn-1-yloxy)phenyl)-4,8-dihydropyrano [3,2-b]pyran-3-carbonitrile (1 mmol, 0.350) with benzyl chloride derivatives (1.1 mmol) and sodium azide (1.5 mmol, 0.0975 g) under various conditions including different solvents (water, dimethylformamide (DMF), methanol and tert-Butyl alcohol), temperatures and ultrasonic in the presence of a catalytic amount of Fe 3 O 4 @CQD@CuI were tested which its results shown in Table 2. The results displayed that water as solvent and ultrasonic condition at 60 °C was the best reaction condition of choices for the production of kojic acid-triazole based dihydropyrano [3,2-b] pyran in click reaction ( Table 2, entry 10). The product was obtained in stirring condition in water with lower efficiency than ultrasonic condition ( Table 2, entry 1). Lowering the temperature and the catalyst values led to low efficiency while no increasing efficiency was observed with increasing them ( Table 2, entries [11][12][13]. After determining the optimal condition, it was used to evaluate the efficiency of the catalyst in the synthesis of new triazole compounds using benzyl halide derivatives in reaction with dihydropyrano[3,2-b]pyrans derivatives containing acetylene group. The results revealed that the products had high efficiency and low reaction time (Fig. 13).
To evaluate the performance of Fe 3 O 4 @CQD@CuI as catalyst for the synthesis of kojic acid-triazole based dihydropyrano-pyran derivatives, the various homogeneous and heterogeneous catalysts containing copper were used for the click reaction between 2-amino-6-(hydroxymethyl)-8-oxo-4-(4-(prop-2-yn-1-yloxy)phenyl)-4,8-dihydropyrano [3,2-b]pyran-3-carbonitrile (1 mmol, 0.350 g), sodium azide (1.5 mmol, 0.0975 g) and benzyl chloride derivatives (1.1 mmol, 0.138 g) under ultrasonic condition in the water as a solvent at 60 °C temperature ( Table 3). The results in Table 3 predicate that Fe 3 O 4 @CQD@CuI is the best catalyst for the synthesis of kojic acid-triazole based dihydropyrano-pyran derivatives. Furthermore, the spent catalyst was characterized after the 5th catalytic cycle using SEM and TEM analyses. The morphology and particle size of the Fe 3 O 4 @CQD@ CuI after the 5th catalytic cycle was not changed based on SEM and TEM images prior and after using in the reaction (Fig. 14). www.nature.com/scientificreports/

Conclusion
In this research, we have designed and synthesized the NMP Fe 3 O 4 @CQD@CuI having carboxylic acid groups and copper iodide salt as an acid high efficiency catalyst for the synthesis of kojic acid based dihydropyrano-pyran and kojic acid-triazole based triazol-dihydropyrano-pyran compounds that favorably combines the properties Brønsted and Lewis acid and advantages of nanomagnetics catalyst in a three-component and the click reactions. The considerable advantages of this method are easily catalyst removal from the reaction medium using an external magnetic field, its reusing capability and high efficiency in lower time reaction.  www.nature.com/scientificreports/  www.nature.com/scientificreports/ www.nature.com/scientificreports/ Figure 11. Proposed mechanism for the synthesis kojic acid based dihydropyrano-pyran using Fe 3 O 4 @CQD@ CuI.