An efficient approach for the green synthesis of biologically active 2,3-dihydroquinazolin-4(1H)-ones using a magnetic EDTA coated copper based nanocomposite

2,3-Dihydroquinazolinone derivatives are known for antiviral, antimicrobial, analgesic, anti-inflammatory, and anticancer activities. However, recent approaches used for their synthesis suffer from various drawbacks. Therefore, we have fabricated a highly efficient magnetic EDTA-coated catalyst, Fe3O4@EDTA/CuI via a simple approach. The ethylenediamine tetraacetic acid (EDTA) plays a crucial role by strongly trapping the catalytic sites of CuI nanoparticles on the surface of the Fe3O4 core. The designed nanocatalyst demonstrates its potential for the catalytic synthesis of 2,3-dihydroquinazolinones using 2-aminobenzamide with aldehydes as the reaction partners. The nanocatalyst was thoroughly characterized through X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), vibrating sample magnetometry (VSM), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), X-ray photoelectron spectroscopy (XPS) and inductively coupled plasma analysis (ICP). The physiochemically characterized nanocatalyst was tested for synthesis of 2,3-dihydroquinazolinones and higher yields of derivatives were obtained with less time duration. Moreover, the catalytic synthesis is easy to operate without the use of any kind of additives/bases. Furthermore, the catalyst was magnetically recoverable after the completion of the reaction and displayed reusability for six successive rounds without any loss in its catalytic efficiency (confirmed by XRD, SEM, and TEM of the recycled material) along with very low leaching of copper (2.12 ppm) and iron (0.06 ppm) ions. Also, the green metrics were found in correlation with the ideal values (such as E factor (0.10), process mass intensity (1.10), carbon efficiency (96%) and reaction mass efficiency (90.62%)).


Introduction
Magnetic nanoparticles have gained great interest in the last few years due to their excellent properties such as low cost, low toxicity, high surface area to bulk ratios, high activity, thermal stability, and the surface modications capability, easy dispersion, and superparamagnetic behavior. [1][2][3] The modication of their surfaces with different amino ligands prevent them from aggregating which leads to stabilized active metal species over the surface. Magnetic recoverable catalysts have a wide range of uses in organic transformations such as C-H activation, 4 coupling reactions, 5-7 reduction reactions, 8 oxidation reactions, 9 and the synthesis of many heterocyclic compounds. 10,11 Moreover, these magnetic nanoparticles can be separated from the reaction mixture very easily using a magnet. Magnetic separable catalysts come out to be a bridge between homogenous and heterogeneous catalysts. 12 Copper is a 3d transition metal whose materials have been widely used in many catalytic reactions due to its various oxidation states from Cu 0 to Cu 3+ . Also, copper-based nanomaterials have a high boiling point of 2562°C , which marks them appropriate for high temperature and pressure conditions. [13][14][15][16] The effective approach for the synthesis of highly robust, selective and low-cost copper based nanoparticles is to create magnetic copper based nanocomposites which have been used in several organic transformation due to their easy separation with low leaching of copper. 17-21 Fe 3 O 4 and copper composites have found many application in many organic transformation such as synthesis of propargylamines using Cu(I)-pybox-Fe 3 O 4 nanocomposites, Fe 3 O 4 @PmPDs@Cu 2 O as a nanocatalyst in the synthesis of 5-phenyl- [1,2,3]triazolo [1,5-c]quinazolines, Cu@DOPA@Fe 3 O 4 as a nanocatalyst in the cross coupling of thiols and aryl halides, Fe 3 O 4 @CS-TCT-Tet-Cu(II) nanocatalyst in the synthesis of N-sulfonyl-N-aryl tetrazoles and 5-arylamino-1H-tetrazoles etc. 22 The development of many heterogeneous catalytic system involving metal-organic frameworks and nanoparticles for the synthesis of various nitrogen containing heterocycles have been extensively reported. 23 2,3-Dihydroquinazolinones are essential nitrogencontaining heterocyclic moieties showing various biological and pharmacological activities such as antiviral, analgesic, anti-inammatory, anticancer and antimicrobial (Fig. 1). [24][25][26][27][28] Numerous procedures are known for synthesizing 2,3-dihydroquinazolin-4(1H)-ones like reductive cyclization of 2-azidobenzamides or 2-nitrobenzamides, 29 quinazolin-4(3H)-ones reduction, 30 condensations of 2-aminobenzamides with benzil, 31 desulfurizations of 2-thioxoquinazolin-4(3H)-ones. 32 While, the most common method involves the condensation of ketones or aldehydes with 2-aminobenzamide in the presence of various acid catalysts like cellulose-SO 3 H, 33 cerium(IV) ammonium nitrate (CAN), 34 p-TSA, 35 Y(NO 3 ) 3 , 36 succinimide-Nsulfonic acid, 37 and ZrCl 4 . 38 However, these methods have various limitations which includes yields in low amounts, long reaction time, use of harmful solvents, complex work-up procedure, using expensive reagents and lack of catalyst reusability. Therefore, it is essential to develop a simple, efficient, green, and sustainable route to synthesize 2,3dihydroquinazolinones.
Our research group has earlier successfully fabricated multiple nanocatalysts to synthesize numerous biologically active organic frameworks such as benzimidazoles, polyhydroquinolines, xanthenes, 1,4-dihydropyridines, and 4Hpyrans. [39][40][41] In the present work, we design a novel, efficient, and magnetically recoverable Fe 3 O 4 @EDTA/CuI nanocatalyst to synthesize 2,3-dihydroquinazolin-4(1H)-ones through condensation of 2-aminobenzamide with different aldehydes. The     relatively stable under the performed reaction conditions giving an excellent yield of the products, and was separated quite easily and reused for six times without much decrease in the % yield.

Design and synthesis of the nanocatalyst
The design and synthesis of the catalyst are shown in Fig. 2. It involves the synthesis of Fe 3 O 4 nanoparticles by coprecipitation method followed by modication of the surface with EDTA, and further CuI was immobilized on the modied support resulting in Fe 3 O 4 @EDTA/CuI.    25 and 57.20 emu g −1 respectively. There is a decrease in M s value when EDTA is coated over Fe 3 O 4, and the value further decreases when CuI is immobilized over Fe 3 -O 4 @EDTA. Also, the external magnet can easily separate the catalyst from the reaction mixture. Moreover, there were no coercivity, hysteresis loop, and remanence detected in any of the prepared nanomaterials, which shows the superparamagnetic nature of all.
Furthermore, CuI existence in the Fe 3 O 4 @EDTA/CuI nanocatalyst was also conrmed by X-ray photoelectron spectroscopy as shown in Fig. 6. The peak binding values at 932.3 eV and 952.2 eV were related to Cu 2p and the values at 619 eV and 632 eV were related to I 3p. The value resembles the reported   data of CuI nanoparticles which also conrms the +1 oxidation state of copper. 44 The values at 710.8 and 724.3 eV are allocated to the spin-orbit split doublet of Fe 2p 1/2 and Fe 2p 3/2 respectively which resembles with the reported values of Fe 3 O 4 . 45 The broadness of the Fe 2p peaks conrms the presence of both oxidation states of iron (Fe 2+ and Fe 3+ ). 46 The peak at 529.8 eV corresponds to O 1s peak of Fe 3 O 4 . Fig. 7 and 8 (Table 1). It was observed that no product was obtained when toluene was used (entry: 1, Table 1). Then solvents such as DMF, DMSO, THF and acetonitrile, which are polar aprotic, were used. It was found that the product formed was 43%, 56%, 11%, and 23% in DMF, DMSO, acetonitrile, and THF respectively (entries: 2-5, Table 1).

Synthesis of 2,3-dihydroquinazolin-4(1H)-ones via
When solvents like EG (ethylene glycol), water, methanol, ethanol were used, no reaction in water was observed (entry: 6, Table 1); while using ethanol and EG, the product formed was 62% and 58% respectively (entry: 8-9, Table 1). Also, no product was formed in neat reaction conditions (entry: 7, Table 1). Then the reaction was reuxed in methanol and ethanol. The yields were 78% and 97% respectively (entry: 10-11, Table 1). The better appropriate solvent which affords the product was ethanol (entry: 11, Table 1). The effect of reaction time on yield was checked, and it was found to be 76% and 97% aer 10 min and 30 min (entry: 12-13, Table 1). The effect of catalyst was also investigated, which shows that on decreasing and increasing the amount of catalyst, the yield observed was 81 and 97% (entry: 14-15, Table 1). Hence, no change was observed in yield on increasing the catalyst amount. When CuI was used, the yield obtained was 56% (entry: 16, Table 1). Hence, the appropriate reaction condition for nanocatalytic synthesis was 20 mg of Fe 3 O 4 @EDTA/CuI reuxed for 20 min in ethanol.
Derivatives of 2,3-dihydroquinazolin-4(1H)-ones were synthesized using the most appropriate reaction conditions as shown in Scheme 1. The excellent yield of the products were obtained in all from the various benzaldehydes (3a-3l). Fig. 10 shows the plausible mechanism for synthesizing 2,3dihydroquinazolin-4(1H)-ones by Fe 3 O 4 @EDTA/CuI nanocatalyst. The rst step involves reaction between 2-aminobenzamide (1) and aldehyde (2) in the presence of catalyst, where catalyst behaves as Lewis acid and interacts with oxygen atom of the carbonyl to increase the electrophilicity of aldehydic carbon to give Schiff base (3) by elimination of water molecule. The next step involves the amide nitrogen attack on electrophilic carbon of the imine followed by proton transfer to obtain 2,3-dihydroquinazolin-4(1H)-ones (4).
Then, we investigated the recyclability of the catalyst. The reaction was setup on a large scale using 5 mmol of reactants and 200 mg of catalyst. At the completion of every reaction cycle, the external magnet helped in separating the catalyst from the reaction mixture. The catalyst was washed with water and ethanol, dried and reused for subsequent reactions. The catalyst was reused six more successions and yield of the product was found to be 83% aer sixth catalytic cycle as shown in Fig. 11. The stability of the material was checked aer six runs by XRD, SEM and TEM which indicates that the structure and morphology of the catalyst remain unchanged (ESI Fig. S1-S3 †). The ICP analysis of the ltrate was carried out aer the removal of the catalyst from the reaction mixture and it was found that leached metal ion concentrations for copper and iron ion are 2.12 ppm and 0.06 ppm respectively which are lower than the authentic concentration of respective ions as per WHO terms. 47 The calculative values of green metrics are shown in Table 2 (detail calculations in ESI †). The current method is green and sustainable as the green metrics are near ideal values. Also, the present catalyst shows better value of metrics than the previous reported methods. Table 3 shows the comparison of Fe 3 O 4 @EDTA/CuI catalyst with various catalysts for the synthesis of 2-(4-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one. It can be seen that the current catalyst has better reaction conditions when compared with other various catalysts.

Preparation of Fe 3 O 4 , Fe 3 O 4 @EDTA, and Fe 3 O 4 @EDTA/ CuI nanocomposites
The Fe 3 O 4 nanoparticles were prepared by co-precipitation method. Briey, 5.6 g of FeCl 3 $6H 2 O and 2.3 g of FeCl 2 $4H 2 O were dispersed in 100 mL of distilled water and stirred for 1 hour at 60°C. Furthermore, 10 mL of ammonia (25%) solution was added dropwise with continuous stirring. The color changed instantly to black, and further, the reaction was stirred for 1 hour at 60°C. The Fe 3 O 4 nanoparticles were separated magnetically and washed with water and ethanol four times to remove any impurities. Lastly, the material was dried in the oven at 60°C for 12 hours.  In 100 mL of distilled water, 1 g of synthesized Fe 3 O 4 was dispersed with 1 g of 2Na-EDTA, and the mixture was sonicated for 30 min. The obtained Fe 3 O 4 @EDTA was isolated magnetically, washed with water followed by ethanol, and then dried in a vacuum oven at 60°C for 12 hours. 500 mg of Fe 3 O 4 @EDTA was dispersed in 20 mL of distilled water and then 100 mg of CuI was added, and the mixture was stirred for 2 hours at room temperature. The nal product was collected using a magnet and washed with distilled water and ethanol many times to eliminate impurities. The obtained catalyst Fe 3 O 4 @EDTA/CuI was dried at 60°C for 12 hours.
3.2 General procedure for the synthesis of 2,3dihydroquinazolin-4(1H)-ones For the reaction, 0.5 mmol of aldehyde, 0.5 mmol of 2-aminobenzamide, 3 mL of ethanol and 20 mg of catalyst were added in a round bottom ask, and the mixture was reuxed under continuous stirring for the given time. The reaction was constantly monitored with the help of thin-layer chromatography. On completion of the reaction, the magnet was used to separate the catalyst from the reaction mixture. The product was puried using column chromatography to afford the nal pure product.

Conclusion
In this work, we have developed a novel and efficient Fe 3 O 4 @-EDTA/CuI catalyst to synthesize biologically interesting molecule 2,3-dihydroquinazolin-4(1H)-ones by reaction between 2aminobenzamide and different aldehydes under green conditions. The method includes advantages like short reaction time, high yield, ambient reaction conditions, no additives, greener pathway, and the excellent value of green chemistry metrics. Furthermore, a magnet can easily collect the nanocatalyst and reuse it six more times with a very slight reduction in its catalytic action.