1 Introduction

Multi-component reactions (MCRs) are those reactions in which three or more reactants come together in a single reaction vessel to form a new product which contains portions of all the components. They have been known for over 150 years (Rotstein et al. 2014). In an MCR, there is a network of reaction equilibria, which all finally flow into an irreversible step yielding the product. MCRs have been proven to be extremely successful in producing molecular complexity in a single synthetic operation, and shown simple procedures, high atom economy, and high selectivity due to the formation of carbon–carbon and carbon–heteroatom bonds in one-pot. The challenge is to conduct an MCR in such a way that the network of pre-equilibrated reactions channel into the main product and do not yield side-products. The result is clearly dependent on the reaction conditions: solvent, temperature, catalyst, concentration, the kind of starting materials, and functional groups. Such considerations are of particular importance in connection with the design and discovery of novel MCRs (Rotstein et al. 2014; Slobbe et al. 2012).

Since heterocyclic compounds are commonly used in different fields of sciences and technology, the preparation of these compounds is an important part of synthetic organic chemistry. 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) and their derivatives are one of the most important classes of MCRs products due to their wide range of biological and pharmacological properties such as antihypertensive, antiviral, antibacterial, anticancer, antitumor, anti-inflammatory agents, α1a-antagonists, neuropeptide Y antagonists, and integral backbones of several calcium channel blockers (Gartner et al. 2005; Nasr-Esfahani et al. 2011; Niknam et al. 2007). The most straightforward procedure for the preparation of dihydropyrimidinones is the one-pot condensation of aldehydes with β-ketoester and urea under acidic conditions (Biginelli reaction). The great potential of DHPMs in pharmaceutical fields has accordingly triggered growing interest in their synthetic study. To improve the Biginelli reaction conditions, various catalysts and reaction conditions have been studied such as Fe3O4@SiO2@Et-PhSO3H (Mobaraki et al. 2014), KAl(SO4)2·12H2O (Azizian et al. 2006), SBSSA (Tajbakhsh et al. 2012), NH4H2PO4/SiO2 (Tayebee et al. 2012), Ce(SO4)2·4H2O (Davoodnia et al. 2014), PhICl2 (Tale et al. 2013), sulfonated carbon (Moghaddas et al. 2012), SnCl2/nano SiO2 (Safaei Ghomi et al. 2013), Im-MNPs (Nazari et al. 2013), PFPAT (Khaksar et al. 2012), TSILs (Fang et al. 2010), Cu(OAc)2 (Kathing et al. 2014), citric acid (Ghorbani-Choghamarani et al. 2013), SiO2–NaHSO4 (Chari and Syamasundar 2004), NaHCO3/MW (Kefayati et al. 2015), Cu(OTf)2 (Pasunooti et al. 2011), Nano-γ-Fe2O3eSO3H (Kolvari et al. 2014), ZBFBSB (Wang et al. 2015), β-cyclodextrin (Liberto et al. 2013), Zn(OAc)2 (Karamat et al. 2010), ethylene glycol (Imtiaz et al. 2012), vitamin B1 (Lei et al. 2010), SiO2–CuCl2 (Kour et al. 2014), SBNPSA (Jetti et al. 2014), PS-PEGOSO3H (Quan et al. 2011), KHSO4 (Tu et al. 2004a, b), AMA (Sharghi and Jokar 2009), H5PW10V2O40/PipSBA-15 (Tayebee et al. 2013), SiO2–SnCl4, and SiO2–TiCl4 (Niknam et al. 2010).

As another important MCR, synthesis of 2-aminopyridine derivatives attracted enormous attention due to their wide applications. The N-heteroaromatic pyridine is prevalent in numerous natural products, pharmaceuticals, and functional materials, and is extremely important in the chemistry of biological systems. Among these compounds, 2-amino-3-cyanopyridine derivatives have been reported to possess remarkable pharmacological properties and activities such as antiviral, anticancer, antitubercular, antimicrobial, A2A adenosine receptor antagonists, anticardiovascular, analgesic, kinase inhibitors, IKK-b inhibitors, carbonic anhydrase inhibitors, and fungicidal activities (Ayvaz et al. 2013; Movassaghi et al. 2007; Sarda et al. 2009). Moreover, 2-amino-3-cyanopyridines are highly reactive compounds. They are extensively utilized as reactant or reaction intermediates, because the cyanofunction of these compounds is suitably situated with common mono or bidentates to form a variety of heterocyclic compounds (Gouda et al. 2013). Therefore, the synthesis of these compounds continues to attract interest in organic chemistry. Various preparation methods for the synthesis of 2-amino-3-cyanopyridines have been reported such as [EtNH3]NO3 (Sarda et al. 2009), MWI (Gouda et al. 2013; Shi et al. 2005), Yb(PFO)3 (Tang et al. 2011), FePO4 (Zadpour and Behbahani 2015), TBBDA (Ghorbani-Vaghei et al. 2013), Ti(dpm)(NMe2)2 (Dissanayake et al. 2014), [Bmim][BF4] (Mansoor et al. 2012), cellulose–SO3H (Mansoor et al. 2014), ultrasonic irradiation (Gupta et al. 2010; Safari et al. 2012), SBTETASA (Niknam et al. 2012), trifluoroethanol (Khaksar and Yaghoobi 2012), [HO3S(CH2)4MIM][HSO4] (Davoodnia et al. 2011), PDTAS (Niknam et al. 2013), and also multiple step procedure using amino acid and refluxing (Girgis et al. 2004).

α-Zirconium phosphate (ZP) is one of the most important compounds in inorganic chemistry, and the layered structure of this material has been used in a variety of different fields (Gan et al. 2014; Sun et al. 2007). The layered structure of ZP consists of zirconium ions in a semiplanar arrangement, located slightly above and below the mean plane, while each Zr4+ ion is connected through the oxygen atoms of phosphate groups from above and below. Three of the four oxygen atoms in the phosphate groups are bonded to three different zirconium atoms. The fourth oxygen atom of the phosphate groups that bonds to a proton, the free –OH group, is pointing into the interlayer region (Chen et al. 2010; Sun et al. 2007). ZP behaves as a unique ion exchanger because of its exceptionally poor aqueous solubility, high thermal stability, resistance to radiation, and abrasive properties (Alhendawi 2014; Naik et al. 2010; Shi et al. 2011). The H+ of the P–OH moiety in ZP can be exchanged for various other ions, which results in the enlargement of the interlayer distance (Cai et al. 2012; Dai et al. 2012; Yang et al. 2011). Several studies pertaining to the successful exchange of the H+ of the P–OH group in ZP with various divalent and trivalent cations have been reported in the literature (Allulli et al. 1976; Clearfield and Kalnins 1976; Giannoccaro et al. 2005; Khare and Chokhare 2012). It has also been reported that ZP possesses excellent selectivity towards Pb2+, Zn2+, and Fe3+ as an ion exchanger (Dash et al. 2015; Zhang et al. 2015). Furthermore, ZP has been reported to exhibit antibacterial activity when it was loaded with Cu2+, Zn2+, or Ce3+ (Cai et al. 2012; Dai et al. 2012; Shi et al. 2011; Yang et al. 2011). Several reports have also appeared in the literature concerning the catalytic activities of ion exchanged materials of this type, including the use of zinc zirconium phosphate (ZPZn) as catalyst in the acetylation of alcohols and phenols and the use of zirconium phosphate–ferric chloride complex and potassium iron zirconium phosphate as catalyst in Friedel–Crafts reaction (1981; Alhendawi et al. 2014; Gawande et al. 2005; Karimi 2015a, b; Khare et al. 2015; Liu et al. 2015).

With growing environmental concerns, use of green and insoluble catalysts or of ecofriendly solvent-free conditions is more demanded. When an insoluble catalyst is used, it can be easily recovered from the reaction mixture by simple filtration and recycled and can be reused several times, making the process more economically and environmentally viable. Furthermore, the reported examples have demonstrated that heterogeneous catalysts typically require easier work-up procedures. With this in mind, and as part of ongoing work towards the development of efficient green catalysts for organic transformations, herein, the use of copper zirconium phosphate (ZPCu) as an efficient catalyst for the mild and convenient two MCRs is reported. This catalyst was characterized by ICP-OES, EDS, XRD, BET, NH3-TPD, Py-FTIR, SEM, and TEM.

2 Experimental

The chemical composition of the ZPCu catalyst was evaluated at different stages of the reaction (i.e., before and after the catalytic reaction) by ICP-OES using an Optima 7300 V ICP-OES spectrometer (PerkinElmer). The samples were ground into a fine powder and analyzed by XRD on a Philips X’pert X-ray diffractometer. The specific surface areas of the samples were determined from their N2 adsorption–desorption isotherms using the Brunauer–Emmett–Teller (BET) method on a Quantachrome ChemBET 3000 instrument. Each sample was degassed at 400 °C for 2 h before being analyzed to remove any adsorbed species from their surfaces. Total acidity of the samples was determined by temperature-programmed desorption of ammonia (TPD-NH3) with a Quantachrome ChemBET 3000. Before the adsorption of ammonia, the samples were pre-treated in He at 250 °C for 30 min and then, 1 h at 350 °C and cooled to 100 °C. Then ammonia was adsorbed on the samples for 1 h. The TPD-NH3 was carried out between 150 and 550 °C, at 10 °C min−1, and analyzed by a thermal conductivity detector (TCD) for continuous monitoring of the desorbed ammonia. Pyridine adsorption was used to determine the acidic sites using FTIR. Prior to the measurements, 20 mg of a catalyst was pressed in self-supporting disc and activated in the IR cell attached to a vacuum line at 350 °C for 4 h. The adsorption of pyridine was performed at 150 °C for 30 min. The excess of probe molecules was further evacuated at 150 °C for 0.5 h. The adsorption–evacuation was repeated several times until no changes in the spectra were observed. The surface morphologies of the α‐ZP and ZPCu materials were studied by SEM on a Philips XL scabbing electron microscope (Philips). TEM images of ZPCu were obtained on CENTRA 100 TEM system (Zeiss). The FTIR spectroscopic measurements were carried out using a JASCO FT/IR (680 plus) spectrophotometer. The spectra were recorded in the range 400–4000 cm−1 using a KBr technique. The Melting points were measured on an Electrothermal IA9100 apparatus and are uncorrected. 1H NMR spectra were recorded on Bruker-Avance 400 MHz spectrometers. The spectra were measured in CDCl3 or DMSO-d6, relative to TMS (0.00 ppm).

2.1 Catalyst Synthesis

The catalyst was prepared according to previously published procedures, with minor modifications (Allulli et al. 1976; Clearfield and Kalnins 1976; Khare and Chokhare 2012; Sun et al. 2007). ZP was prepared according to the following procedure. ZrOCl2∙8H2O (5 g) was heated at reflux in a solution of H3PO4 (50 cm3, 12 mol L−1) for 24 h. The resulting mixture was cooled to ambient temperature to give a suspension, which was filtered, and the filter cake was then washed with a solution of H3PO4 (0.1 mol L−1) until the filtrate was free of chloride ions. The filter cake was then washed several times with distilled water until the pH of the filtrate was neutral. The solid was then collected and dried in an oven at 110 °C for 12 h (Sun et al. 2007). ZPCu was prepared through an ion‐exchange reaction (Allulli et al. 1976; Clearfield and Kalnins 1976; Khare and Chokhare 2012). Briefly, ZP (3 g) was dispersed in deionized water (50 cm3) at 50 °C, and the resulting suspension was treated with a solution of Cu(OAc)2 (100 cm3, 0.1 mol L−1) in water (excess amount of Cu2+). This mixture was then heated at reflux for 4 days. It is noteworthy that the acetate ion performed effectively as a base to keep the hydrogen ion concentration in solution sufficiently low to achieve high loadings of the catalyst. A complete exchange between the cations and the hydrogen ions of the P–OH groups could not be achieved in less than 3 days or at temperatures below 80 °C (Yang et al. 2011). The resulting slurry was filtered hot to give a light white solid, which was washed with distilled water until no Cu2+ ions could be detected in the filtrate (i.e., until the filtrate was colorless). The solid product was then dried at 100 °C for 8 h before being calcined at 600 °C for 4 h to give the final product, ZPCu, as a pale green solid (Scheme 1).

Scheme 1
scheme 1

Summarized procedure for ZPCu preparation

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2.2 General Procedure for the Preparation of DHPMs

A mixture of aldehydes (1 mmol), EAA (1 mmol,), urea or thiourea (1.1 mmol), and catalyst (1 mol%) was stirred at 80 °C in oil bath under solvent‐free conditions for the specified time. The completion of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then, cool water was added and stirred for 5 min. The crude product was collected by filtration and washed with ice-cold water. The residue was dissolved in a minimum amount of hot EtOH and then cooled to room temperature to afford the pure product. The catalyst was insoluble by filtration. All products are known compounds and were characterized by comparing their M.p, IR, and 1H NMR spectra with those found in the literature (Kolvari et al. 2014; Liberto et al. 2013; Pasunooti et al. 2011; Wang et al. 2015).

2.3 General Procedure for the Preparation of 2-Amino-3-Cyanopyridines

A mixture of aldehyde (1 mmol), ketone (1 mmol), malononitrile (1 mmol), ammonium acetate (2 mmol), and catalyst (1.5 mol%) were stirred in one-pot at 60 °C for the appropriate time. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was washed with EtOH and the catalyst was removed. The corresponding pure solid product was obtained through recrystallized from hot EtOH affording the 2-amino-3-cyanopyridine derivatives. All products are known compounds and were characterized by comparing their M.p, IR, and 1H NMR spectra with those found in the literature (Gupta et al. 2010; Mansoor et al. 2012, 2014; Niknam et al. 2012; Safari et al. 2012).

2.4 Recyclability Studies of Catalyst

To examine the recyclability of the catalyst, the used ZPCu was recovered from the reaction media and reused. For recycling, after the first use, the catalyst was separated from the reaction mixture by centrifugation, washed sequentially with ethanol and water before being dried at 110 °C for 2 h, and then activated at 450 °C for 2 h. The catalyst regeneration procedure in both mentioned MCRs is quite the same; hence, to shorten the manuscript, only the data of regenerated ZPCu in the synthesis of DHPMs are represented.

3 Results and Discussion

3.1 Characterization

The EDS and ICP-OES analyses of ZP and ZPCu are shown in Table 1 and Fig. 1. The results obtained in the current study for ZPCu were compared with those reported previously in the literature (Allulli et al. 1976; Clearfield and Kalnins 1976; Khare and Chokhare 2012). Our results revealed that there was a negligible leach of copper ions into the reaction media after the reaction (i.e., following the first use of the catalyst).

Table 1 Element contents of ZPCu (atm.%) and physical properties of the catalysts before and after reaction
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Fig. 1
figure 1

EDS spectra of ZPCu

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Figure 2 shows the powder XRD patterns of the ZP and ZPCu materials. The results show some characteristic reflections in the 2θ range of 5°–40°. The diffraction peak in ZP at 2θ ~ 12° was assigned to a d002 basal spacing of 7.6 Å between the planes, which was consistent with the patterns previously reported for ZP and its derivatives with a hexagonal crystal system (Sun et al. 2007). It shows that the d-spacing of the (002) plane of ZPCu had increased, which indicated that the Cu2+ ions had intercalated into the interlayer of ZP and increased the d002 basal interlamellar spacing of ZP from 7.6 to 8.8 Å. It is well known that the ion radii of Cu2+ (0.72 Å) and hydrated Cu2+ (4.19 Å) are smaller than the basal spacing of ZP (7.5 Å) (Liu et al. 2009). These results, therefore, indicated that Cu2+ ions had inserted into the interlayer of ZP and increased the basal spacing of the modified ZP after the exchange (Allulli et al. 1976; Clearfield and Kalnins 1976; Khare and Chokhare 2012). Taken together, these data indicated that ZPCu had been formed successfully. The XRD pattern of the ZPCu catalyst after the seventh run showed that the basal spacing of ZP was about 8.5 Å, which was only a little larger than that of the fresh ZPCu catalyst. This increase may have occurred because of the presence of less Cu2+ on the surface of ZP, and an increase in the number of water molecules between the layers following the seventh run (i.e., Cu2+ ions may have been washed off during the regeneration of the catalyst, Table 1).

Fig. 2
figure 2

XRD patterns of powder ZP (down), ZPCu fresh (middle), and ZPCu after the seventh run (up)

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Figure 3 shows the N2 adsorption–desorption isotherm of ZPCu, as a representative example, in the relative pressure range (p/p0) of 0.01–1.0. The surface area of ZPCu was determined to be 121.6 m2 g−1. The isotherm for ZPCu shows three adsorption stages. The first of these stages was observed at p/p0 < 0.44, whereas the second stage was observed in the range of 0.37 < p/p0 < 0.98, and the third stage was observed at higher relative pressures (p/p0 > 0.98). The N2 adsorption–desorption isotherm of ZPCu exhibited a typical “type IV” isotherm shape with a distinct hysteresis loop, which is characteristic of a mesoporous material (Sing 1985). The hysteresis loop (type H3) is associated with the occurrence of capillary condensation in the mesopores, which indicates the presence of a mesoporous structure in the ZPCu catalyst. The observed increase in adsorption at the higher p/p0 value indicated the presence of larger mesopores in the sample (Karimi 2015a). The surface area of ZPCu after the seventh run was found to be 72.3 m2 g−1.

Fig. 3
figure 3

N2 adsorption–desorption isotherm of ZPCu

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Pyridine adsorption was used to determine the acidic sites using FTIR. The main bands observed over the samples are assigned according to the literature data (Tyagi et al. 2006). Pyridine desorbed FTIR spectra of the ZPCu shows the strong bands at 1632 and 1541 cm−1, indicating typical pyridinium ion. The band at 1488 cm−1 is a combination band between those at 1541 and 1444 cm−1, corresponding to Brønsted and Lewis acid sites, respectively. Figure 3b shows the Py-FTIR spectra of the catalyst after the seventh run. It clearly represents that due to the replacement of Cu2+ on the surface of the catalyst with H+ during the catalyst regeneration process, the Lewis acid sites are reduced (bant at 1444 cm−1 was reduced). On the other hand, the amount of Bronsted acid sites was increased (bant at 1632 cm−1 was reduced) (Fig. 4).

Fig. 4
figure 4

Pyridine-desorbed FTIR spectra of ZP (up), ZPCu fresh (down), and ZPCu after the seventh run (middle)

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Total acidity of the samples was determined by temperature-programmed desorption of ammonia (TPD-NH3) with a Quantachrome ChemBET 3000. TPD-NH3 provides a quantitative estimation of the total number of acid sites and the distribution of acid strengths. Because of the strong basicity of NH3 gas, it was expected that all acid sites on the catalysts interact with NH3. The total amount of NH3 desorbed after saturation permits the quantification of the number of acid sites on the surface, while the position of the peak, desorption temperature, indicates the strength of the catalyst, i.e., the higher temperature of desorption, the stronger the acid strength (Karimi 2015a). The TPD-NH3 curves of ZPCu are shown in Fig. 5. The ZPCu desorbed ammonia in a wide range of temperatures from 237 to 631 °C, which mostly corresponds to the medium and the strong acidic sites.

Fig. 5
figure 5

NH3-TPD profile of ZPCu

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The NH3 desorption peak at temperatures below 250 °C belongs to the physisorption/chemisorptions of NH3 molecules on weak acidic sites. The peak at about 250–450 °C shows the existence of intermediate strength acidic sites, and finally, the peak at 450–538 °C demonstrates the presence of strong acidic sites on the surface of ZPCu. Figure 5 shows that the desorption of ammonia starts at almost 237 °C, centered at 350. The NH3-TPD curves subsequently decreased with further increase in temperature and almost complete at 631 °C. This indicates that ZPCu contains a considerable number of acid sites which is attributed to the presence of Cu2+ groups on the surface of zirconium phosphate layers and make it suitable solid acid catalyst. The extent of desorptions is found to be ca. 1.9 mmol NH3 g−1 of catalyst. A TPD experiment was carried out after the seventh cycle by recovering the catalyst, to magnify the difference from the fresh catalysts (Table 1).

The SEM image of ZP (Fig. 6a) revealed the presence of hexagonal plates with well-defined shapes and very smooth surfaces. Figure 6b, c shows the SEM images of ZPCu. These images revealed that the structure of ZPCu was much less ordered than that of ZP, and that the ZPCu particles had aggregated to form both sheets and spheres of different shapes and sizes.

Fig. 6
figure 6

SEM images of regular morphology of prepared a ZP, b, c ZPCu fresh, and d after the seventh run

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Figure 7 shows the TEM images of ZPCu. It shows that ZPCu catalyst retained the original morphology of ZP (layered structure) and that the particles were approximately 150 nm in size. These images also showed nanoparticles of different sizes on the smooth surface of the ZP. The presence of metallic crystal nanoparticles on the surface of ZP indicated that the copper deposited on the surface of the ZP had agglomerated. Similar observations have also been reported for zinc and cerium with ZP (Cai et al. 2012; Dai et al. 2012).

Fig. 7
figure 7

TEM images of regular morphology of prepared a–c ZPCu fresh (different magnification) and d after the seventh run

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Figures 6d and 7d show the SEM and TEM images of the catalyst following its seventh run, respectively. Both of these images showed that the sheets and particles had conglomerated to a much greater extent following the seventh run because of the process used to regenerate the catalyst.

3.2 Synthesis of DHPMs

To obtain the best reaction conditions, the reaction of benzaldehyde (1 mmol), ethyl acetoacetate (EAA) (1 mmol), and urea (1.1 mmol) was examined as a simple model under different conditions (Table 2). The reaction was carried out in various solvents as well as solvent-free conditions (Table 2, entries 1–8). As it is shown, under these conditions (Table 2, entries 1–7), the reactions were sluggish and low-to-moderate yields were obtained in the tested solvents. For this reaction, it proceeded most readily to give the highest yield of the product (1a) under solvent-free conditions (Table 2, entry 8). The yield and time were markedly influenced by the reaction temperature. Increasing the reaction temperature up to 80 °C enhanced the yield and reduced the required time, below 80 °C, the reaction proceeded slowly giving a relatively low yield, and no improvement was observed above 80 °C (Table 2, entries 9–13). The excess amount of the catalyst (Table 2, entries 14–16), or more reaction time (Table 2, entries 17–20) did not sharply influence the yield of the reaction, but decreasing them reduced the yield. In the absence of catalyst, the reaction failed to give the desired product even after prolonging reaction time (Table 2, entry 21). Hence, the best result was obtained when the reaction was carried out at 80 °C using 1 mol% of ZPCu under solvent-free conditions (Table 2, entry 8).

Table 2 Reaction between urea, EAA, and benzaldehyde under different conditions
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After optimization the reaction conditions, the generality of the procedure for the Biginelli adducts was investigated with various aldehydes, urea, or thiourea. A library of substituted DHPMs was obtained in good-to-excellent yields in appropriate reaction times under solvent-free conditions (Table 3). As demonstrated in Table 3, aromatic aldehydes bearing either electron-donating (ED) or electron-withdrawing (EW) groups were reacted easily to produce the corresponding DHPMs in good-to-excellent yields, and no undesirable side-products were observed. Interestingly, the condensation protocol was fairly general, and using this procedure, various functional groups survived during the course of the reaction. Furthermore, the conditions are mild enough to perform this reaction with acid-sensitive aldehydes such as furfuraldehyde and cinnamaldehyde (Table 3, entries 18 and 19) without the formation of any side-products, which are normally observed either in the presence of protic or Lewis acids. The aromatic aldehydes with EW substituents (Table 3, entries 6–17) were converted to the related DHPM derivatives in shorter reaction times than those with ED substituents (Table 3, entries 2–5). However, when aliphatic aldehydes (Table 3, entries 19–21) were used as the starting materials, the yield dropped significantly because of the lower activity of the carbonyl group in aliphatic aldehydes or due to decomposition or polymerization (Chari and Syamasundar 2004). In addition, the steric effects did show significant effect on the yields and reaction times. For example, ortho-substituted aromatic aldehydes (Table 3, entries 3, 6, 11, 15) with more steric hindrance gave lower yields in comparison to para-substituted (Table 3, entries 5, 8, 13, 17). It is noteworthy that the methodology was also successful when urea replaced with thiourea and the yields of the related products were fair (Table 3, entries 22–26).

Table 3 Synthesis of DHPMs using ZPCu under solvent-free conditions
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Based on this results and previous reports (Moghaddas et al. 2012; Nasr-Esfahani et al. 2011; Safaei Ghomi et al. 2013; Tayebee et al. 2012), a plausible reaction mechanism for this synthesis is represented (Supplementary information, Scheme S1). To explore the advantages of this ZPCu-catalyzed reaction, the results of the present method under the optimized conditions were compared with those reported in the literature for Biginelli reactions mediated by other catalysts (Table 4). Although some of the other catalysts gave marginally higher conversions, however, they required longer reaction time, higher temperature, and a higher amount of catalyst. The present method used a small amount (1 mol%) of an environmentally friendly catalyst under solvent-free conditions and required a relatively short reaction time. In addition, the ZPCu catalyst was easily separated from the reaction mixture after work-up and used several times.

Table 4 Comparison of efficiency of various catalysts in synthesis of (1a)
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The reusability of the catalyst was also investigated with the same model reaction under the optimized conditions. Upon completion of the reaction, the catalyst was recovered according to the procedure described in the experimental section and reused. As shown in Table 5, during the recycling experiment with fresh reactants, under the same reaction conditions, no considerable change in the activity of the catalyst was observed for at least six consecutive runs which clearly demonstrate the stability of the catalyst for these conditions in the Biginelli reaction.

Table 5 Catalyst reused for the synthesis of 1a
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3.3 Synthesis of 2-Amino-3-Cyanopyridines

To find out the suitable conditions for the reaction, a series of experiments were performed for the synthesis of 2-amino-4,6-diphenylnicotinonitrile (2a) as a model compound (Table 6). The reaction was performed in various solvents to identify the best solvent condition. Several classic solvents such as EtOH, MeOH, CH3CN, H2O, DMF, n-hexane, CHCl3, THF, 1,4-dioxane, toluene, and also solvent-free conditions were examined. The experimental results showed that the yield of the product is higher under solvent-free conditions (Table 6, entry 11). To further improvement of the reaction yield, five experiments in different temperatures were performed (Table 6, entries 11–15). It was observed that the application of a lower temperature gave the corresponding product in lower yield. The reaction provided little amounts of product without catalyst (Table 6, entry 20). The optimal conditions were determined as that the reaction was catalyzed by 1.5 mol% of ZPCu under solvent-free conditions at 60 °C in 60 min (Table 6, entry 11).

Table 6 Synthesis of 2-amino-4,6-diphenylnicotinonitrile (2a) under different conditions
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To delineate the scope and generality of our new protocol, this methodology was examined by the reaction of several substituted aldehydes and acetophenones (Table 7). The reaction succeeded well, providing the corresponding 2-amino-4,6-diphenylnicotinonitrile derivatives in fair-to-high yields, demonstrating the generality of the method and its well tolerance of both EW and ED substituents on the both aromatic rings. The electronic effect seemed to have a clear influence on the reaction, since the EW groups on the different aromatic rings resulted in better yields than ED groups. We also studied this condensation reaction with 2-substituted benzaldehyde, finding that the reaction time was longer and yields were somewhat lower than other aldehydes which were possibly attributed to the steric hindrance (Table 7, entries 4, 5). Surprisingly, the aliphatic aldehyde (hexanale) and the aliphatic ketone (acetone) gave no products. Obviously, the reactivity of aldehydes is the key factor for this one-pot transformation.

Table 7 Synthesis 2-amino-3-cyanopyridines using ZPCu under solvent-free conditions
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Based on this results and previous reports (Ghorbani-Vaghei et al. 2013; Khaksar and Yaghoobi 2012; Shi et al. 2005; Tang et al. 2011), a plausible reaction mechanism for this synthesis is represented (Supplementary information, Scheme S2). To show the value of the present work in comparison with reported results in the literature, the results of ZPCu catalyst for the synthesis of 2-amino-4,6-bis-(4-chlorophenyl)-nicotinonitrile (2m) was compared with results obtained by other groups (Table 8). As it can be seen from this table, ZPCu acts as an effective catalyst with respect to reaction temperature, time, and yield.

Table 8 Comparison of efficiency of various catalysts in synthesis of 2m
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4 Conclusions

In summary, we have reported the catalytic performance of water-insoluble ZPCu in two MCRs. The catalyst was characterized by various methods and results showed good agreement with the literature. These conditions are compatible with some acid-sensitive functional groups. The attractive features of these procedures are short reaction times, mild reaction conditions, higher yields and no side reactions, ease of preparation and handling of the catalyst, green aspects by avoiding toxic catalysts and solvents, the recyclability of the catalyst, and simple experimental procedure. This convenient technique is the most effective compared with the existing methods for the synthesis of coumarins and its derivatives. Further investigation on the new application of ZPCu as a Lewis acidic catalyst in other MCRs is extremely ongoing in our laboratory.