A Nano-sized Nd–Ag@polyoxometalate Catalyst for Catalyzing the Multicomponent Hantzsch and Biginelli Reactions

For the first time the catalytic activity of AgNdSiW11, was examined in two named reactions, namely Hantzsch and Biginelli reactions. A simple, eco-friendly and highly efficient one-pot synthesis of polyhydroquinoline derivatives via Hantzsch multicomponent reactions (MCRs) involving cyclocondensation of differently-substituted aldehydes, β-ketoesters or dimedone, active methylene compounds, and ammonium acetate as a source of nitrogen, in the presence of AgNdSiW11 as a catalyst in EtOH/H2O under reflux conditions in high yields was successfully achieved. Furthermore, the catalytic performance of AgNdSiW11 was also successfully tested in the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones via Biginelli MCR involving cyclocondensation of differently-substituted aldehydes, ethyl acetoacetate and urea as source of nitrogen in the presence of AgNdSiW11 under reflux conditions in EtOH/H2O. This prolific combination of Ln and POMs inaugurates a powerful class of catalysts for the different chemical transformations, which overcomes key limitations of previously established salts and Lewis acidic metals-based catalysts under low catalyst loading, the use of water scavengers, dry solvents and additives for facilitating the specialized experimental setups commonly employed to the organic reactions.


Introduction
The application of efficient, easy to recover, reusable and eco-friendly catalysts to comply with the principles of green chemistry is a key priority for synthetic organic chemists [1]. Polyoxometalates (POMs), as anionic earlytransition-metal oxide clusters, are a well-known and efficient class of catalysts with a unique set of characteristics such as high redox potential, high thermal stability, strong acid-base properties, high proton mobility and good solubility in polar solvents [2][3][4][5][6][7]. Owing to their numerous surface oxygen atoms, POMs have been viewed as inorganic multidentate ligands which can coordinate to metals [8]. One strategy to improve the catalytic activity of POMs is using them as inorganic ligands via their combinations with d-and f-metal ions. Lacunary POMs are good candidates for the construction of d-f heterometallic compounds, since they have a large number of different potential and versatile coordination sites and modes. The incorporation of lanthanoid (Ln) ions into the lacunary site of the POM framework enhances the catalytic properties [9]. However, examples of POM-based d-f heterometallic compounds are relatively rare [10,11], and the synthesis of new POM-based d-f heterometallic compounds is still a challenge. On the other hand, Ag ? ions have flexible coordination modes and high affinity to O donors, which may easily form covalent links between Ag ? and POMs.
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Thus, Ag ? is a suitable synthon as metal ion for the construction of POM-based d-f heterometallic compounds. Recently, Zhang et al. [12] successfully synthesized and characterized a two-dimensional (2D) purely inorganic 4d-4f heterometallic compound [La(H 2 O) 8  In continuation of our interest in exploring POMs catalysis in organic transformations leading to the heterocyclic systems [13][14][15], the purely inorganic 4d-4f heterometallic compound attracted our attention. In our latest papers, we clearly demonstrated the role of lanthanoid ions and silver ions in improving the catalytic activity of POMs [16][17][18]. In this study, the combination of POM catalysts with the lanthanoid and silver ions, is expected to be more promising due to synergism effect.
Herein, we wish to report the preparation and characterization of purely inorganic A multicomponent reaction (MCR), which is occasionally referred to as a ''Multi component Assembly Process'' (MCAP), is a chemical reaction in which three or more compounds react in a sequential and one vessel manner to afford highly selective products in which the majority of the atoms of the starting materials are included in a single product [19,20]. Their atom economy, efficacy, mild reaction conditions, high convergence and associated step economy along with their general compatibility with green solvents validate and justify their places in the toolbox of sustainable synthetic methodologies [15].
1,4-Dihydropyridines (DHPs) are an important class of biologically and pharmacological potential compounds, which are derived from a pyridine structure. These compounds exhibit intriguing biological properties and are commonly employed as L-type calcium channel blockers [21], as in the prescribed drug nifedipine and some other some commercially available drugs with a 1,4-dihydropyridine core (Fig. 1) [22]. The synthesis of DHPs was introduced by Arthur Hantzsch in 1882, is the efficient, environmentally benign, less time consuming and cost-effective method [23,24]. Accordingly, DHPs are frequently synthesized via Hantzsch MCR, involving various aldehydes, beta ketoesters and a source of nitrogen such as ammonium acetate (Scheme 1) [25]. One of the main disadvantages of the Hantzsch DHP synthesis is the long reaction times needed for full conversion. However, this problem has been circumvented by performing the reaction under microwave irradiation (MWI) [26,27].
We are interested in heterocyclic chemistry [53][54][55][56][57][58][59], especially in the synthesis of heterocyclic systems via MCR [60][61][62][63] being conducted under heterogeneous catalysis in aqueous media [64]. In the last few decades, our group has been engaged in heteropolyacids and their polyoxymetalate-catalyzed reactions. The results of these efforts along with other activities have been included in several review articles [13]. Based on the points mentioned above and in continuation of our interest in exploring green heterogeneous catalysts for organic transformations leading to the heterocyclic systems, herein we report our successful attempt to apply AgNdSiW 11 as an efficient and reusable catalyst in the synthesis of polyhydroquinoline derivatives via the Hantzsch reaction (Scheme 1) and dihydropyrimidones via the Biginelli reaction (Scheme 2).

Results and Discussion
In continuation of our above-mentioned interest in the catalyzed synthesis of heterocyclic compounds [64] via MCR [60] using HPAs and their polyoxometalates as efficient catalysts [65] under green conditions [66], in this research, we tried to extend our research activities, focusing our attention to examine the catalytic activity of a virgin heteropoly acid, AgNdSiW 11 in the synthesis of a heterocyclic system via MCRs. Initially, we prepared a-K 8 SiW 11 O 39 Á13H 2 O by modification of previously reported method [67]. AgNdSiW 11 was prepared according the procedure described in (Ref. [12]), but Nd(NO 3 ) 3 Á6H 2 O was used instead of La(NO 3 ) 3 Á6H 2 O. Infrared spectroscopy, ICP, and elemental analysis results show that this catalyst is isostructural with the compound reported in (Ref. [12]) (Fig. 3). In this compound, two mono-substituted {SiW 11 Nd(H 2 O) 4 O 39 } 2 clusters (abbreviated to SiW 11 Nd) polymerize together to form a dimer and also the dimers are linked by Ag ? and Nd 3? heterometallic cations displaying a 2D network. Presence of the Ag ? and Nd 3? heterometallic cations and the mono-substituted (SiW 11 Nd) 2 dimer with the high charge density and big volume compared with the SiW 12 polyanions exert considerable influence on the catalytic activity of this compound.
Therefore, we used this inorganic catalyst in the Hantzsch MCR involving 4-chlorobenzaldehyde, dimedone, ethyl acetoacetate, and ammonium acetate as model reaction expecting to give the corresponding ethyl 4-(4chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate 4a. First, we conducted the reaction in water/ethanol under reflux condition but in the absence of any catalyst. This un-catalyzed reaction, proceeded sluggishly (monitored by TLC, using 7:3 n-hexane/ ethyl acetate as eluent) and only trace amount of the desired expected product was detected in a long reaction time. This attempt showed the necessity of the presence of the catalyst in the above mentioned Hantzsch MCR. It is worthwhile mentioning that the effects of other polar and non-polar solvents such as H 2 O, EtOH, EtOH/H 2 O, EtOAc, CH 3 CN and CH 2 Cl 2 , as well as solvent-free conditions were examined in the model reaction (Table 1). Having the prepared AgNdSiW 11 in hand, we conducted the model reaction in the presence of catalytic amounts of aforementioned HPA in H 2 O/EtOH under reflux condition. The progress of the reaction was monitored by TLC (using 7:3 n-hexane/ethyl acetate as eluent), showing the model reaction proceeded smoothly and cleanly, consuming the starting materials and producing the expected product. The best result was obtained when the reaction was conducted using 0. 15 Table 1. Under secured optimal reaction conditions, the scope, limitations and generality of this strategy was tested for the synthesis of ethyl 4-(4-chlorophenyl)-2,7,7-trimethyl-5oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.
The generality of method was established by using differentlysubstituted benzaldehydes bearing either electron-releasing or electron-withdrawing moieties in the ortho, meta, and para positions (Scheme 1). In all cases the corresponding polyhydroquinoline derivatives were obtained in good to excellent yields in relatively short times without the formation of any detectable by-products. The results are shown in Table 2.
Encouraged by these results, we examined the role of AgNdSiW 11 in the Biginelli reaction, which is another important MCR named reaction. The reaction of 4-chlorobenzaldehyde, ethyl acetoacetate and urea in the presence of AgNdSiW 11 was chosen as the model reaction. The progress of the reaction was monitored by TLC (using 7:3 n-hexane/ethylacetate as the mobile phase and silicagel as the stationary phase). The best result was obtained when the above reaction was performed in EtOH/H 2 O under reflux conditions to give 3,4-dihydropyrimidin-2(1H)-one 7a in 67% yields.
The substrate scope of this reaction was also tested. We used differently-substituted benzaldehydes bearing either electron-releasing or electron-withdrawing substituents in the ortho, meta, and para positions with ethyl acetoacetate and urea or thiourea under already established optimized reaction conditions (Scheme 1). In all cases, the corresponding 3,4-dihydropyrimidin-2(1H)-one derivatives 7ag were obtained in good to excellent yields in relatively short times without the formation of any detectable byproducts. The results are summarised in Table 3.
A proposed mechanism for the catalytic activity of AgNdSiW 11 in the Hantzsch reaction is illustrated in Scheme 3. Initially, the bonding complex was generated by catalyst. Then, a Knoevenagel condensation of the 1,3-dicarbonyl compound with the aldehyde affords an a,b-unsaturated carbonyl compound 8 while the reaction of ammonia with another equivalent of the 1,3-dicarbonyl compound generates an enamine 9. We believe that the rate  . A proposed mechanism for the formation of dihydropyrimidines 7 is shown in scheme 4. Here, also initially, the bonding complex was formed by catalyst. Subsequently, the acylimine intermediate 11 is generated by the reaction between an aldehyde and urea. On the other hand, condensation of enol 12 with the acylimine generates an intermediate which is subjected into cyclization followed   [80] by dehydration to give the corresponding dihydropyrimidines 7 [82].
The comparison showed that our designed and selected catalyst is very effective according to several criteria: it gives the desired products in a shorter reaction time; the catalyst is reusable; and the EtOH/H 2 O reaction medium is a benign one. Curiously, the persistence of this work, which is introducing a catalyst with potential application for improving organic transformations and specifically in the synthesis of two distinct and important Scheme 3 Suggested mechanism for Hantszch reaction Scheme 4 Suggested mechanism for Biginelli reaction heterocyclic systems dihydropyridines (DHPs) and dihydropyrimidin-2(1H)-ones were provided via two well-established and recognized MCR Hantzsch, and Biginelli reactions, respectively.

Catalyst Reusability
To clarify whether AgNdSiW 11 could act as a heterogeneous catalyst and in view of the distinction of the reusability especially in large-scale production, the reusability of AgNdSiW 11 was studied. To resolve, the model reaction in Hantzsch reaction, it was conducted in the presence of the freshly prepared catalyst. Upon completion of the reaction (indicated by TLC), it was separated by centrifuging, washed, dried and used the second reaction run. The reusability of the catalyst was examined for three successive reaction runs. This observation showed that the catalyst could be recovered and recycled up to three reaction runs without significant loss in its catalytic activity (Fig. 4).  [59], the vibration bands are redshifted. The m(W-Ob-W) vibration is split into three bands due to the insertion of neodymium (Nd) atom with the corresponding reduction in symmetry. Additionally, the band centered at 3411 cm -1 is attributed to the m(OH) vibration of water molecules (Fig. 5). The morphology of catalyst was studied by scanning electron microscope (SEM) analyses. As shown in Fig. 6, the presence of nano size particles is confirmed.

Synthesis of Polyhydroquinoline: General Procedure
A mixture of the differently-substituted benzaldehydes (0.5 mmol), dimedone (0.5 mmol), ethyl acetoacetate (0.5 mmol) and ammonium acetate (1 mmol) was stirred in the presence of freshly made AgNdSiW 11 (0.15 mol%) in EtOH/H 2 O (4 mL) under reflux conditions. Upon completion of the reaction (monitored by thin layer chromatography (TLC), the reaction mixture was cooled to room temperature. The, catalyst was separated by centrifugation and washed with a mixture of hexane and petroleum ether and dried at room temperature to obtain the corresponding products 4a-g.

Synthesis of 1,4-Dihydropyridines (DHPs): General Procedure
A mixture of substituted benzaldehydes (0.5 mmol), ethyl acetoacetate (1 mmol) and ammonium acetate (1 mmol) was stirred in the presence of AgNdSiW 11 (0.15 mol%) in EtOH/H 2 O (4 mL) under reflux conditions. Upon, completion of the reaction (monitored by TLC) the reaction mixture was cooled to room temperature. The catalyst was separated by centrifugation, washed with hexane and petroleum ether and dried at room temperature to give the corresponding products 5a-f. Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones: General Procedure A mixture of the differently benzaldehydes (0.5 mmol), ethyl acetoacetate (1 mmol), urea or thiourea (0.5 mmol) in the presence of AgNdSiW 11 (0.15 mol%) was stirred in EtOH/H 2 O (4 mL) under reflux condition. Upon completion of reaction (monitored by TLC), the reaction mixture was cooled to room temperature. Then, the catalyst was separated by centrifugation and washed with hexane and petroleum ether at ambient temperature. The corresponding products 7a-g were identified by comparison of their melting points as well as their FTIR spectra.

Conclusion
In summary, we have presented a highly efficient and green protocol for MCR synthesis of polyhydroquinolines, 1,4dihydropyridines and 3,4-dihydropyrimidin-2(1H)-ones as biologically potent compounds employing AgNdSiW 11 as a green, heterogeneous and recyclable catalyst in EtOH/ H 2 O in a one-pot fashion. This strategy offers substantial improvements in the reaction rates and yields. Herein, it was demonstrated the catalytic activity of AgNdSiW 11 for the first time. It can be reused for several times with high efficiency. This catalyst was effectively employed in two MCR named reactions, namely the Hantzsch and Bignelli reactions, to give different polyhydroquinolines and pyrimidones. This strategy benefits from using water/ ethanol as solvent and that the catalyst which can be reused several times giving high yields within a relatively short reaction time. Our protocol benefits from the merits of heterogeneous catalysis as well as being doubly green through using water/EtOH as solvent. Thus, this protocol can be well applicable in industry as well as academia.