ZnO nanoparticles: An efficient reagent, simple and One-Pot Procedure for Synthesis of Highly Functionalized Dihydropyridine Derivatives

: A new and efficient one-pot synthesis of dihydropyridones derivatives by four-component reaction between cyanoacetamide, aryl aldehydes, and ethyl acetoacetate with ammonium acetate using nano ZnO is described. The reaction was performed in ethanol under reflux conditions and afforded good yields of products. of atom of four [3+1+1+1] [2+2+1+1] atom fragments. 8,9 Synthesis of 4-aryl-3-cyano-2,5-dihydro pyridin-2-one


Introduction
Substituted dihydropyridones derivatives are important intermediates in the pharmaceutical, dye and photo industries. 1 pyridones are of interest because of the occurrence of their saturated and partially saturated derivatives in biologically active compounds and natural products such as NAD nucleotides, pyridoxol (vitamin B 6 ), and pyridine alkaloids. 2 Due to their π-stacking ability, some pyridines are used in supramolecular chemistry. 3 Some examples are used as pharmaceuticals (as antimalarial, vasodilator, anesthetic, anticonvulsant, and antiepileptic), dyes, additives (as antioxidant), agrochemicals (as fungicidal, pesticidal, and herbicidal), veterinary (as anthelmintic, antibacterial, and antiparasitic), and also in qualitative and quantitative analysis [4][5][6][7] . So far, the most common synthetic methods for the preparation of pyridine ring systems involve: transformation of another ring, and cyclizations classified on the basis of the number of ring atoms in each of the components being cyclized: from six ring atoms by N-C α , C α -C β , or C β -C γ bond formation; by formation of two bonds, from [ 8,9 Synthesis of 4-aryl-3-cyano-2,5-dihydro pyridin-2-one derivatives under solvent-Free conditions we reported 10 .
Nanomaterials have attracted considerable interest in the last decade because of their unique properties in physics and chemistry as well as their potential industrial applications. Among these materials, ZnO is an important semi-conducting material, having a wide range of properties. The size and morphology of ZnO nanoparticles have great influences on their performances. Recently, efforts have been made for the synthesis of ZnO particles with controlled morphologies. Wurtzite-type ZnO crystals are used for a wide variety of industrial applications, such as semiconductors 11 catalysts 12 , room-temperature UV lasers 13 , solar cells 14 and sensors 15 .

Experimental
Melting points were determined with an Electrothermal 9100 apparatus. Elemental analyses were performed using a Costech ECS 4010 CHNS-O analyzer at analytical laboratory of Islamic Azad University Yazd branch. 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 500.1 and 125.8 MHz, respectively. 1 H and 13 C NMR spectra were obtained on solution in CDCl 3 using TMS as internal standard. Column chromatography was performed with Merck silica gel 60, 230-400 mesh. The chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification.

Results and Discussion
Herein we report a new and efficient one-pot synthesis of polysubstituted dihydropyridones derivatives by four-component reaction between cyanoacetamide, aryl aldehydes and ethyl acetoacetate with ammonium acetate using nano ZnO. The reaction was performed in ethanol under reflux conditions and afforded good yields of products. (Figure 1).  The reaction course without ammonium acetate in the absence of zinc oxide a complex mixture was obtained from which no product was isolated. The reaction course in the presence of ammonium acetate without zinc oxide afforded the product in lower yield and longer reaction time. Using nano ZnO afforded the product in higher yield and shorter reaction time. The structure of compounds A and B was deduced from their elemental analyses and their IR, 1 H, and 13 CNMR spectra data. The mass spectrum of compound 7A displayed the molecular ion peak at m/z = 329 as the base peak. The 500 MH Z 1 H NMR spectrum of compound 7A exhibited a D 2 O-exchangable broad signal at 10.28 ppm for NH proton, and displays one sharp line (δ 2.31 ppm ) for the methyl group. Ethyl protons were observed as a triplet ( 3 J HH = 7 H Z ) at 1.06 ppm and a quartet at 3.98 ppm. Two doublet were observed respectively at 4.13 and 4.18 ppm for methine protons. Although the mechanistic details of the above reaction are not known, a plausible mechanism may be advanced to rationalize product formation.
Resumably a intermediate 3 formed from michael addition of product 1 the addition of cyanoacetamide with aryl aldehydes using nano ZnO and product 2 the addition of ethyl acetoacetate with ammonium acetate which could undergo stepwise cyclization to produce A by elimination of NH 3. The amide tautomer is considerably more stable. Admittedly the exchangeable peak in the 1H NMR spectrum is very high for a NH peak, and would appear to be more consistent with a OH peak. The A product is finally converted to B by oxidation ( Figure 2

Conclusion
In summary, here we reported a four-component reaction between cyanoacetamide, aryl aldehydes and ethyl acetoacetate with ammonium acetate using nano ZnO. The reaction was performed in ethanol under reflux conditions and afforded good yields of products. The present method carries the advantage that not only is the reaction performed under neutral conditions but also that the substances can be mixed without any activation or modification. nano ZnO was prepared as previously described in the literature. 16