Ag2O/GO/TiO2 Composite Nanostructure: An Ecient Heterogeneous Catalyst for one Pot Synthesis of Bis (Dihydropyrimidinone) and Tetrahydro-4H-chromenes Derivatives

The simple and efficient synthesis reaction was used for preparing Bis (dihydropyrimidinone) derivatives through Biginelli condensation reaction of terephthalic aldehyde, 1, 3-dicarbonyl compounds and (thio) urea or guanidine and tetrahydro-4H-chromenes via one pot condensation of aromatic aldehydes, malononitrile and dimedone with Ag 2 O/GO/TiO 2 composite nanostructures as a catalyst. The structural functionalities and morphological observations of catalyst were obtained using characterization techniques of field emission scanning electron microscopy (FESEM), X-ray diffraction (XRD), Fourier transfer infrared (FT-IR) spectroscopy and transmission electron microscope (TEM). The structures of Bis (dihydropyrimidinone) and tetrahydro-4H-chromenes confirmed by FT- IR, NMR and mass spectroscopy. Excellent yields of the products, simple reaction process and simple work-up are attractive features of these effective synthesis methods.


Introduction
Graphene oxide (GO), consisted of two carbon sheets with closed lattice structure has gathered widespread interest as a catalyst and catalytic support due to presence of surface bound active functional sites, large surface area, and excellent thermal and mechanical properties. [1] Primary cause for high activity of GO is the presence of hydroxyl, carboxylic and epoxy groups, which shows high acidity, excellent oxidizing properties, good conductivity, etc. [2][3][4] Organic transformations are catalyzed by graphene oxide utilizing its acidic protons or its strong oxidizing ability and has shown potential to replace the traditional metal catalyzed pathways. Numerous one pot syntheses such as a-aminophosphonate synthesis, benzimidazole synthesis, epoxidation, Michael addition, aldol condensation etc., are accelerated by surface bound hydroxyl and carboxylic acid groups in GO. [5][6][7][8][9] Catalytic activity of graphene oxide refere to presence of functional groups further, the properties of graphene can be amazing by incorporating other functional groups on the GO sheets. Found that synthesis method could impact the properties of graphene oxide [10][11][12].
Here, we have studied the effect of metal addition to GO on the synthesis of bis (dihydropyrimidon) derivatives. We have chosen multicomponent Biginelli reaction between aryl aldehyde, urea and methyl acetoacetate for synthesis of dihydropyrimidinones as a model reaction.
With the development of nanotechnology, catalysts made of transition metals have drawn a lot of attention due to their application in various areas including organic transformations, rechargeable batteries, and wastewater treatment [13]. Transition metals (Co, Fe, Ni, Mo, Mn, and Zn, etc.) show advantages such as being inexpensive, non-toxic, and abundant in the earth [14]. The applications of N^O (ethylimino-methyl) phenol Fe(II) and Co(II) complexes in ethylene oligomerization catalysis and their structural elucidation were studied by Ngcobo et al. [15]. In artificial photosynthetic systems, hydrogen is generated with molecular catalysts of Co, Ni, Fe, and Mo [16]. Du et al. carried out theoretical and experimental studies on metal-organic frame derived (M=Fe, Ni, Zn, and Mo) which were doped into Co9S8 nano arrays as an efficient electro catalyst for water splitting [14].
Recently, noticeably growth in the applications of heterogeneous catalysis in organic reactions to carry out synthetic transformations as a consequence of its significance in terms of enviroeconomical and practical aspects [17].
The Biginelli reaction is one of the well-designed methodologies used for the synthesis of dihydropyrimidinone (DHPM) or thione derivatives, an important family of compounds known for their diverse pharmacological properties, which can act as antibacterial, antiviral, and calcium channel modulators as well as anticancer and antihypertensive agents. The reported biological activities of DHPMs encourage research groups to produce structurally diverse libraries of bioactive heterocycles [18][19][20][21]. solvent-free techniques, [28] grinding techniques, [29] and many new catalysts. [30] Nevertheless, most protocols have severe limitations, for example, low yields, high cost and catalyst loadings, and low catalyst recovery and recyclability.
Furthermore, questions about the efficacy of solvent-free and/or catalyst-free reactions and the effect of solvent versus solvent free conditions still lead to discussions in the scientific community. To overcome these drawbacks, which have thrown chemists toward the search of new, better, and benign conditions for the biginelli reactions. Transition metal nanoparticles have received a great deal of attention due to a viable alternative to conventional materials in the field of catalyst. Such a new nano catalysts for biginelli reaction are Nano-TiCl4.SiO2 [31], Fe3O4 nanoparticle supported Ni (II) complexes [32], Niobium Nano catalyst, [33] Fe3O4-MWCNT nanocomposite [34], Mesoporous ZnO/AlSBA-15 (7) Nanocomposite [35], Magnetic core-shell Carrageenan moss/Fe3O4, [36] Mesoporous silica nano composite, [37] Fe3O4@ PVA polymeric magnetic nano composite [38] and Magnetic nanoparticles supported imidazolium-based ionic liquids [39].
A combination of metallic and natural compounds in a single nano composite material has been good idea for catalytic application for several decades. High thermal stability, high acidity, and unique nano metric porous network of the zeolites made them the best candidates for introducing an acidic function. There are several catalytic reactions where metal-zeolite composite materials have been efficiently used. [51] In recent years, several researchers have sought the effect of trimetallic catalysts made of transition metals on catalytic capabilities. However, no studies have been found which survey the synthesis of Ag2O/GO/TiO2 composite nanostructures.
In continuation of our interest in the synthesis of new nanostructure compounds, [52][53] herein, we report the preparation of Ag2O/GO/TiO2 structures on graphene materials and the catalytic activity of this new zeolite nano catalyst was evaluated for the synthesis of a wide range of bis (dihydropyrimidone) benzene and tetrahydro-4H-chromene derivatives with high structural diversity through the reaction protocols. A comparison of the efficiency of this new nano catalyst with that of other known transition metal nano catalysts has revealed interesting and promising results.

Instrumental techniques
The crystalline phase of the as-synthesized sample was identified by X-ray diffraction (XRD) measurements by the means of a Ultime IV Multipurpose X-ray diffractometer spectrum was obtained using a Perkin Elmer BX-II spectrophotometer. Surface morphology was determined from field emission scanning electron microscopy (FESEM, Zeiss SIGMA VP-500) equipped with side detectors including energy-dispersive X-ray spectroscopy (EDS) and high-resolution elemental mapping to examine elemental compositions. The morphological features of the sample were investigated with a Zeiss (EM10C -Germany) transmission electron microscope (TEM) operating at 100 kV. All yields refer to isolated products. Products were characterized by comparison of their physical data such as IR, 1H NMR and 13C NMR spectra with authentic samples. By using TMS as internal standard, NMR spectra were recorded in CDCl3 on a Bruker Advance DPX 250 MHz spectrometer.
Determination of the products' purity in the course of the reaction were monitored by TLC on silica gel poly gram SILG/UV 254 plates. Mass spectra were recorded on a MS model 5973 Network apparatus at ionization potential of 70 eV.

Synthesis of Ag2O Nanoparticles
A wet chemical technique was utilized to synthesize Ag2O nanoparticles according to the literature [32]. In a typical synthesis process, 80 mL of a 0.005 M silver nitrate (AgNO3) aqueous solution was heated 60 ˚C . After that, 20 mL of a 0.025 M sodium hydroxide aqueous solution was added drop by drop to the prepared AgNO3 solution under continuous magnetic stirring at 60 ˚C for 2 h. After cooling to room temperature, the formed precipitate was collected by a centrifuge with a speed of 3000 rpm, washed with ethanol several times, and dried at a constant temperature of 40 ˚C at 24 h.

Synthesis of Ag2O/GO/TiO2 Composite Nanoparticles
Ag2O/GO/TiO2 composite nanoparticles were synthesized through the sol-gel method according to a process reported by Xiao et al. [54]

Typical procedure for the preparation of bis (dihydropyrimidone) derivatives (4a-4g)
A mixture of the aldehyde (2 mmol), 1, 3 dicarbonyl (2 mmol), urea (3 mmol), ethanol (5 drops) and catalyst (0.1 mmol) was taken in a round bottom flask, heated at 80˚C. The reaction is monitored by Thin Layer Chromatography. After completion, ethanol added and the catalyst was separated by filtration and the solvent was evaporated to obtain the solid product. It is then recrystallized from ethanol. The yield of product was calculated from re-crystallized weight, based on aldehyde. The product was characterized by 1 H NMR, 13

Results and discussion
In our attempts to develop a facile one-pot protocols, firstly we focused on the facile condensation of aldehyde (2 mmol), 1, 3 dicarbonyl ester (2 mmol), urea (thiourea) (3 mmol) and catalyst (0.1 mmol) at room temperature and in the solvent free condition. This protocol cause to synthesis of bis (dihydropyrimidon) benzene derivatives in good yields and short reaction times. Table 1 summarizes the results for reactions of terephthalic aldehyde with various derivatives of 1 and 2. We initially examined the reaction of acetylacetone (1a) with urea (2a) and terephthalic aldehyde (3) in the presence of Ag2O/GO/TiO2 under microwave irradiation conditions at 100 0 C (Scheme 1). Experiments showed that small amount of catalyst are enough for the reaction to complete in short reaction times (as indicated by TLC). Alternatively, we didn't see any products in the absence of catalyst. The structure of product 4e in was elucidated by spectroscopy methods and its purity was confirmed by elemental analysis. The optimized conditions utilize a 1: 1: 1.5: 0.1 ratio of di aldehyde, 1,3-dicarbonyl compounds, thiourea and nano catalyst ( Table 1). The procedure is shown to be equally efficient when thiourea is replaced with urea or guanidine. In addition, it can be concluded from both 1 H NMR and 13 C NMR spectra of the product that the reaction is stereospecific loading to exclusive formation of one the meso or dl diastereoproducts from which the meso product is shown here for the simplicity.
Further, the product formed with the addition of distilled water with continues mixing of reaction mixture at room temperature in 20 min. After the completion of reaction, the residue was taken into ethanol and filtered. The crude product is obtained by evaporating the filtrate.
Recrystallization of the crude product led to the isolation of crystalline solid products in short reaction time and high product yield.
With this successful and efficient three-component reaction, synthesis of diverse tetrahydro-4H-chromene derivatives was undertaken. The aromatic aldehydes consist of electronwithdrawing and electron donating groups were found to be equally effective to produce the products in good yields (Table 2). It seems that the role of Ag2O/GO/TiO2 nano composite in this protocol is the help to formation of carbanion form malononitrile and dimedone to reaction with aromatic aldehyde derivatives.
Phase compositions of as-synthesized nanoparticles were identified using the X-ray diffraction (XRD) technique.  The surface chemical composition of the as-synthesized sample was investigated by FT-IR spectroscopy. Fig. 3 shows the FT-IR pattern of Ag2O/GO/TiO2 composite nanoparticles in the range of 450-4000 cm -1 . It can be seen in Fig. 2 that, due to Ti-O stretching in TiO2 lattice, the absorption band appears at 716.64 cm -1 . The characteristic band at 2331.95 cm -1 is ascribed to the stretching modes of carboxyl (C=O) groups. The band observed at 2828.11 cm -1 also corresponds to the C-H stretching frequency. The surface morphology of the as-synthesized sample was observed using FESEM micrographs. FESEM images of Ag2O/GO/TiO2 composite nanoparticles in two different magnifications along with the corresponding histograms of particle size have been illustrated in Fig. 4. The FESEM image shown in Fig. 3a indicates a relatively uniform distribution from spherical-like particles with an average diameter of about 300 nm (Fig. 4c). It can be seen in  (Fig. 4d). Such a formed architecture revealed more available surface areas compared to that with simple spherical structures resulting in more improved performances for potential applications such as synthesis catalyst.   According to figures, it can be said that the particles have Irregular geometric shapes. This method not only preserved the simplicity one-pot condensation, but also remarkably improved the yields (>80%) of products in shorter reaction times as against the longer reaction times required for other catalysts after the addition of a low catalyst concentration. The procedure gives the products in good yields and avoids problems associated with solvent use (cost, handling, safety and pollution), and easy experimental work-up procedure, hence, it is a useful addition to the existing methods.

Acknowledgment
The current study was partially supported by the Islamic Azad University Ahvaz Branch. The authors would like to thank the Research Council for their generous support of this work. Figure 1 Bis (dihydropyrimidinone) (1) and tetrahydro-4H-chromene (2) derivatives Figure 1