An Efficient Synthesis of Functionalized 3-( α-amidobenzyl )-4-hydroxycoumarin Derivatives by ZnO Nanoparticles Promoted Condensation Reaction Between Aromatic Aldehyde , 4-hydroxycoumarin , and Amides

An efficient and green protocol for the synthesis of 3-(α-amidobenzyl)-4-hydroxycoumarin derivatives by one pot, three component coupling reaction of aromatic aldehyde, 4hydroxycoumarin, and amides has been developed using ZnO nanoparticles (NPs) as the catalyst. The procedure is formed in high yields, short reaction time and an environmentally friendly specificity.


INTRODUCTION
Multi-component reactions have been attracting much interest from synthetic chemists because they provide simple one-pot routs for the synthesis of complex molecules from simple and easily available starting materials.These processes are single-step and don't require separation and purification of intermediates and so save time, energy and raw materials 1 .Recently, heterogeneous catalysts have attracted the attention of researchers due to their economic and industrial significance and published reports indicate that they scored over homogeneous catalysts.Among these, nanoscale heterogeneous catalysts are highly preferred as they offer high surface area and low-coordinated sites, which are responsible for the higher catalytic activity [2][3][4] , having the advantage of easy product purification and reusability of the catalyst.The synthesis of coumarins and their derivatives has attracted considerable attention from organic and medicinal chemists for many years as a large number of natural products contain this heterocyclic nucleus.They are widely used as additives in food, perfumes, cosmetics, pharmaceuticals 5 and optical brighteners 6 and dispersed fluorescent and laser dyes 7 .1][12][13] The existing methods for the synthesis of 3-substituted 4hydroxycoumarins include direct synthesis of the target compound [14][15][16][17] , or C3-alkylation/substitution of 4-hydroxycoumarin. 18Recently, we reported the reaction of 4-hydroxycoumarin, aromatic aldehydes, and acetonitrile in the presence of chlorosulfonic acid to produce 3-acetamido-alkyl-4hydroxycoumarin derivatives. 19,20also we reported the reaction of 4-hydroxycoumarin, aromatic aldehydes and amides in the presence p-toluene sulfonic acid in solvent-free conditions to produce 3-(á-amidobenzyl)-4-hydroxycoumarin derivatives 21 but these methodologies have been associated with some shortcomings such as long reaction times, and difficulty in recovery and reusability of the catalysts.[24] Considering the above reports and in continuation of our research on multi-component reactions, 25,26 Herein we have researched for threecomponent coupling of 4-hydroxycoumarin 1, aryl aldehydes 2, and amides 3, in the presence of ZnO nanoparticles as heterogeneous catalyst to the synthesis of 3-(α-amidobenzyl)-4-hydroxycoumarin derivatives 4 (Scheme 1).

RESULTS AND DISCUSSION
Firstly, in order to optimize the reaction conditions, the model reaction was carried out by using 4-hydroxycoumarin, 4-chlorobenzaldehyde, and acetamide under solvent-free conditions in the presence of different nanoparticle as catalysts and the results are listed in Table 1 .
We examined this reaction in the presence of various nanoparticle catalysts in hand including Fe 3 O 4 nanoparticles, MgO nanoparticles, NiO nanoparticles, ZnO nanoparticles (Table 1).It was showed that ZnO nanoparticle was the most efficient catalyst for the reaction in Solvent-Free condition (Table 1, entry 6).However, only a trace amount of the product was formed in the absence of catalyst (Table 1, entry 1).
Afterward, optimization of catalyst amounts was carried out in the model study by using different amounts of the ZnO NPs.The higher yield was obtained with increasing the amount of catalyst from 5 mol% to 15 mol%.However, further increase of the molar amount of the catalyst from 15 mol% to 25 mol% did not significantly increase the yield of the product (Figure 2).Hence, the optimum concentration of ZnO NPs was chosen 15 mol% in the model reaction.
To improve the yield of the target product, we carried out the test reaction in presence of various solvents and the results are presented in Table 2.As can be seen from this table, solventfree conditions accelerated the rate of reaction and also high yields were obtained for all products.
To study the scope of the reaction, a series of aldehydes and amides were employed.The results are shown in Table 3.In all cases, aromatic aldehydes substituted with either electron-donating or electron-withdrawing groups underwent the reaction smoothly and gave the products in good yields.It could also be concluded that the aldehydes bearing electron-withdrawing groups required shorter time and gave higher yields (Table 3).[21] Although it is not clear how ZnO acts as a

Table 3. Three-component reaction of aromatic aldehydes, 4-hydroxycoumarin and amides catalyzed by ZnO NP
catalyst for the reaction, on the basis of the surface of metal oxides exhibit both Lewis acid and Lewis base character 27 and according to the literature survey, [28][29][30] the suggested mechanism for the formation of the products is shown in Scheme 2.
The reusability of the catalyst was tested in the synthesis of 3-(α-amidobenzyl)-4hydroxycoumarin, as shown in Figure 2 dried in an oven at 100 o C for 15 min prior to use and tested for its activity in the subsequent run.The catalyst was tested for 4 runs.It was seen that the catalyst displayed very good reusability (Figure 3).(Figure 3)

EXPERIMENTAL
Melting points were determined with an Electrothermal 9100 apparatus.Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer.Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV.IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1 H and 13 C NMR spectra were recorded on Bruker DRX-500 Avance spectrometer at in DMSO-d 6 solution using TMS as internal standard.The chemicals used in this work purchased from fluka (Buchs, Switzerland) and were used without further purification.

Synthesis of nano-ZnO
Zinc oxide nanoparticles was prepared as previously described in the literature 31 .In a typical procedure, zinc acetate (9.10 g, 0.05 mol) and oxalic acid (5.4 g, 0.06 mol) were combined by grinding in an agate mortar for 1 h at room temperature.Afterwards, the formed ZnC 2 O 4 _ 2H 2 O nanoparticles were calcinated at 450 o C for 30 min to produce ZnO nanoparticles under thermal decomposition conditions.The morphology, structure and size of the samples were investigated by Scanning Electron Microscopy (SEM).Fig. 4 indicates that the original morphology of the particle was approximately spherical with the diameter varying between 20 and 35 nm.

General procedure
A mixture of 4-hydroxycoumarin (1.0 mmol), aromatic aldehyde (1.0 mmol), amide (1.0 mmol), and nano-ZnO (15 mol %) was heated at 110 ºC for 120-135 min.After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature.The solid residue was dissolved in hot ethanol and centrifuged to separate the catalyst.By recrystallization from ethanol, pure products were obtained.

Scheme 2 :Table 2 .
Scheme 2: Suggested pathway for the formation of compounds 4a-j