A novel base-metal multifunctional catalyst for the synthesis of 2-amino-3-cyano-4H-chromenes by a multicomponent tandem oxidation process

A novel base-metal multifunctional nanomagnetic catalyst is prepared by the immobilization of tungstate anions onto γ-Fe2O3 supported with imidazolium moieties. The (γ-Fe2O3-Im-Py)2WO4 was fully characterized using FT-IR, XPS, TEM, FESEM, ICP, TGA, VSM and XRD and used as a multifunctional heterogeneous catalyst for the synthesis of 2-amino-3-cyano-4H-chromenes via a multicomponent tandem oxidation process starting from alcohols under solvent-free conditions. During this process, tungstate catalyzes the oxidation of a wide range of alcohols in the presence of TBHP as a clean source. The in-situ formed aldehydes are condensed with malononitrile and β-dicarbonyl compounds/naphthols/4-hydroxycumarin through promotion by pyridine and imidazolium moieties of the catalyst. By this method, a variety of 2-amino-3-cyano-4H-chromenes are generated in good to high yields from alcohols as inexpensive and easily available starting materials. The catalyst is recovered easily by the aid of an external magnetic field and reused in five successive runs with insignificant decreasing activity.

www.nature.com/scientificreports/ β-dicarbonyl compounds or activated phenols 31 . Numerous modified catalysts have been used for the elaboration of 2-amino-3-cyano-4H-chromenes and their derivatives [32][33][34][35][36][37] . Most of the reports suffer from drawbacks e.g., long reaction times, difficult workup procedures, use of unrecyclable catalyst and afford only moderate yields of the products. 2-Amino-3-cyano-4H-chromenes can also be prepared from alcohols via multicomponent TOP reactions. This method passes through three sequential steps: (1) oxidation of alcohols to aldehydes which requires an oxidizing catalyst, (2) Knoevenagel condensation of the in-situ formed aldehydes with malononitrile, (3) Michael addition of β-dicarbonyl compounds followed by cyclization reaction. The last two steps can be promoted by acidic and/or basic catalysts. Based on a literature survey, there is a few reports on the preparation of 2-amino-3-cyano-4H-chromene starting from alcohol [38][39][40][41] . Within these reports, there is only one report on using a bifunctional catalyst for the preparation of these targeted scaffolds 41 . These methods suffered from several drawbacks such as using expensive oxidizing agent, requiring pH adjustment, time-consuming catalyst isolation, limited activated nucleophiles/alcohols and long reaction time.
The high selective and controllable oxidation of alcohols to corresponding aldehydes is one of the predominant and challenging reactions in synthetic chemistry 42,43 . The classical oxidation methods include the use of stoichiometric amounts of strong oxidants such as chromium (VI) or manganese (VII) reagents 44,45 and concentrated HNO 3 46 which are environmentally hazardous and produce large amounts of toxic wastes. A green protocol to replace the classical method for oxidation reaction is using oxidation metal catalysts [47][48][49] . However, while various catalytic systems including molybdenum 50 , manganese 51 , iron 52 , palladium 53 , rhenium 54 , ruthenium 55 , and copper 56 , have been well explored, catalytic systems based on tungsten have been particularly received a great deal of attentions to achieve high efficiency and selectivity in the oxidation of alcohols 57,58 . As there is a difference in solubility of tungstate anion and organic substrates, the use of ionic liquids containing tungstate anions has attracted much attention for the oxidation of alcohols due to the unique property of ionic liquids (ILs) as a phase transfer catalyst under organic-inorganic media [59][60][61][62] . On the other hand, immobilization of tungsten species onto solid supports has been evolving to overcome the difficult separation of catalyst and products under similar homogeneous conditions. Along this line, several heterogeneous imidazolium-based ILs containing tungstate anions have been introduced for the selective oxidation of alcohols [63][64][65] .
Recently, we have prepared two new magnetically separable functionalized Pd-N-heterocyclic carbene (NHC) starting from supported imidazolium salts on magnetic iron oxide (MNPs) and reported their applications in several organic transformations 66,67 . In our reported catalysts, we have profited from the presence of two nitrogen atoms in imidazole for the immobilization of imidazole onto a MNPs as a solid support on one side and then functionalization of supported imidazolium salts on the other side. Following our attempts for the developing multifunctional heterogeneous catalysts in organic reactions [68][69][70] , herein, we have tried to design a new base-metal multifunctional catalyst from supported imidazole onto MNPs for the generation of 2-amino-3-cyano-4H-chromenes via a three-component TOP starting from alcohols. For this purpose, at first the free nitrogen of supported imidazole was functionalized with pyridine by the reaction with 3-(chloromethyl) pyridine hydrochloride and then the chloride anion in the resulting imidazolium ILs was exchanged with tungstate to produce (γ-Fe 2 O 3 -Im-Py) 2 WO 4 (Fig. 1). In this catalyst, we predicted that tungstate anions will promote  www.nature.com/scientificreports/ the selective oxidation of alcohols to aldehydes and pyridine will activate Knoevenagel condensation-Michael addition-cyclization reaction of in-situ formed aldehydes with malononitrile and dimedone.

Experimental
General information. All Chemicals and solvents were bought from Merck Chemical Company. The product purity and the reaction progress were investigated by TLC using silica gel polygram SILG/UV254 plates. The Fourier transform infrared (FT-IR) spectra were recorded on a Shimadzu Fourier Transform Infrared Spectrophotometer (FT-IR-8300). X-ray photoelectron spectroscopy (XPS) analyses were accomplished using a VG-Microtech Multilab 3000 spectrometer, equipped with an Al anode. The deconvolution of spectra was performed by using Gaussian Lorentzian curves. The content of W in the catalyst was determined by OPTIMA 5300DV ICP analyzer. The transmission electron microscopy (TEM) analysis was performed using Philips EM208S operating at 100 kV. FESEM were achieved using a TESCAN MIRA3. Thermo-gravimetric analysis (TGA) was carried out using TA-Q600. The vibrating sample magnetometer (VSM) analysis was performed using Lake Shore Cryotronics 7407. X-ray diffraction (XRD) analysis was performed using XRD Philips PW1730. Melting points were measured by an electrothermal 9100 apparatus. www.nature.com/scientificreports/ was added to the reaction mixture. (γ-Fe 2 O 3 -Im-Py) 2 WO 4 was isolated using an external magnet, washed with EtOAc (2 × 5 mL) and EtOH (2 × 5 mL), vacuum dried, and recycled for the next run. The combined organic layer was then dried using Na 2 SO 4 . After solvent evaporation, a crude product was obtained. The pure product was achieved by column chromatography on silica gel eluting n-hexane/EtOAc (10:2).    (Table 4, Figs. 10 and 11). After cooling the reaction mixture to ambient temperature, EtOAc (10 mL) was added and the catalyst was collected by an external magnet. It was washed with EtOAc (2 × 5 mL), EtOH (2 × 5 mL), dried and reused for the next run under the same reaction conditions. The combined organic solvents were vacuum evaporated to produce a crude product. Column chromatography on SiO 2 eluting with n-hexane/EtOAc (7:3) produces the pure product. The products were characterized by 1 H NMR spectra (Supplementary Figs. S1-S14).
ICP analysis of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 indicated that 0.35 mmol (0.064 mg) tungstate was immobilized on 1 gr of this compound. The size and morphology of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 were studied using TEM (Fig. 4) and FESEM (Fig. 5). The TEM and FESEM images of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 exhibit the development of uniform sphere-shaped nanoparticles. The average particle size of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 was assessed as 12.4 nm using a size distribution histogram (Fig. 4c). Energy-dispersive X-ray spectroscopy (EDS) was done to approve the presence of each element in this compound. The EDS spectrum (Fig. 5c) displays characteristic signals referring to carbon, nitrogen, oxygen, silicon, iron and tungsten, which shows the immobilizing of WO 4 -Im-Py on the surface of the MNPs. Moreover, elemental mapping was performed to realize the spreading of the elements present in the (γ-Fe 2 O 3 -Im-Py) 2  Thermal stability of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 was analyzed by thermogravimetry (TGA) under inert atmosphere (nitrogen) using 10 °C/min heating slope in the range of 20 to 810 °C. TGA curve of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 (Fig. 7) demonstrates the two-step compound decomposition. A 1.1% weight loss can be observed below 219 °C, which is due to removal of physically adsorbed water molecules. In the second stage, 5.1% mass loss can be observed at 219-730 °C due to the decomposition of organic species supported on the MNPs surface. TGA curve also approves the fruitful loading of organic moiety on the surface of MNPs.  Table 1). The best result was accomplished using 2 mol% of the catalyst and 6 equivalents of TBHP under solvent-free conditions at 90 °C.
To test the generality of this protocol, a diversity of primary and secondary alcohols was allowed to be oxidized under obtained optimum reaction conditions. As shown in Table 2, benzyl alcohols (primary and secondary) were selectively oxidized to aldehydes or ketones in good to high yields (entries 1-18) without any overoxidation    With successful alcohol oxidation, we studied the utility of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 in the synthesis of 2-amino-3-cyano-4H-chromenes via a multicomponent tandem oxidation process (Fig. 9). Thus, the reaction between benzyl alcohol, malononitrile and dimedone was selected as a model reaction to find the optimum amount of the catalyst (Table 3, entries 1-4). The best result was reached using 5 mol% of the catalyst (Table 3, entry 4). www.nature.com/scientificreports/    Figure 14. Role of the catalyst in the synthesis of 2-amino-3-cyano-4H-chromene from benzyl alcohol. www.nature.com/scientificreports/ The reactions of a variety of aromatic/aliphatic alcohol, malononitrile and dimedone were studied using optimum reaction conditions (Fig. 10, Table 4). Benzyl alcohol having electron-withdrawing or -releasing groups underwent the reaction with malononitrile and dimedone with high efficiency to give 2-amino-3-cyano-4Hchromenes in good to high yields. Based on these results, the reaction progress was not sensitive to the electron density of the substrates. Several substituents on the benzyl alcohol such as methoxy, methyl, nitro, chloride and bromide were remained intact during the reaction (Table 4, entries 1-10). The reaction of furfuryl alcohol as a heteroaromatic alcohol and cinnamyl alcohol as an α,β-unsaturated alcohol progressed well (Table 4, entries 11 and 12). 1-Octanol as an aliphatic alcohol was also condensed with malononitrile and dimedone successfully ( Table 4, entry 13). Moreover, the reaction of β-dicarbonyl compounds such as cyclohexane-1,3-dione, pentane-2,4-dione, methyl acetoacetate and ethyl acetoacetate were investigated using the present method and desired products were obtained in good yields (Table 4, entries [14][15][16][17]. The reactions are clean without formation of any side products especially the overoxidation products such as carboxylic acids or esters, which can be formed from alcohols during oxidation reaction. These observations showed the high catalytic activity and selectivity of the catalyst. In addition, the applicability of this protocol was evaluated for the activated compounds such as α-naphthol, β-naphthol and 4-hydrxycoumarin (Fig. 11) and the products were obtained in good to high yields.
To prove the role of the catalyst during the oxidation reaction, the oxidation reaction of benzyl alcohol was assessed in the presence of (γ-Fe 2 O 3 -Im-Me) 2 WO 4 (pyridine-free catalyst), γ-Fe 2 O 3 -Im-Py (tungstate-free catalyst) and γ-Fe 2 O 3 (Figs. 12 and 13). It was found that the reactions were proceeded in 98, 27 and 27% yields, respectively ( Table 5, entries 1-3). These results showed the special effect of tungstate in the oxidation reaction and any role of pyridine in this process. A similar reaction in the presence of sodium tungstate produced the desired product in low yield (24 h, 41%) ( Table 5, entry 4), which showed the activation effect of supported imidazolium species on the tungstate groups. Moreover, the reaction under catalyst-free conditions or in the presence of pyridine produced only a trace amount of the product in 24 h (Table 5, entries 5 and 6). The oxidation reaction of benzyl alcohol in presence of (γ-Fe 2 O 3 -Im-Py) 2 MoO 4 and γ-Fe 2 O 3 -Im-Py-VO 3 , varying two different oxidizing anions, was also examined (Table 5, entries 7 and 8) and the same results as in the presence of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 were obtained.
To demonstrate the role of the catalyst in the TOP synthesis of 2-amino-3-cyano-4H-chromene (Fig. 14), the model reaction was surveyed with (γ-Fe 2 O 3 -Im-Me) 2 WO 4 as the pyridine-free analogues catalyst (Fig. 12). The product was obtained in a moderate yield (50%), which shows the importance of the pyridine effect on the Knoevenagel condensation-Michael addition-cyclization reaction of the in-situ formed aldehyde with malononitrile and dimedone (Table 6, entry 2).
The effect of the catalyst in the Knoevenagel condensation-Michael addition-cyclization step of the synthesis of 2-amino-3-cyano-4H-chromenes was also studied by performing the reaction of benzaldehyde, malononitrile and dimedone (Fig. 15) using (γ-Fe 2 O 3 -Im-Py) 2 WO 4 , γ-Fe 2 O 3 -Im-Py (tungstate-free catalyst) and γ-Fe 2 O 3 -Im-Me (tungstate and pyridine-free catalyst) (Fig. 12, Table 7). Any effect of tungstate was not observed in the Knoevenagel condensation-Michael addition-cyclization reaction. Therefore, in this step, the most active site of the catalyst should be pyridine and imidazolium moiety.
A plausible mechanism was estimated for the reaction based on our results and proposed mechanisms in the literature [81][82][83][84] . Firstly, aldehydes are produced from alcohols by the dehydration in the presence of TBHP catalysed by tungstate ions. In the next step, the catalyst enables the formation of dicyanoolefins (A) by Knoevenagel condensation of in-situ formed aldehydes with malononitrile. Then, Michael addition of enolate of dimedone (B) to dicyanoolefins leads to the formation of C, followed by cyclocondensation and tautomerization to form 2-amino-3-cyano-4H-chromenes (Fig. 16). During this process, imidazolium cations activate electrophiles (aldehyde and malononitrile) by hydrogen-bond formation between the carbonyl and nitrile groups with  www.nature.com/scientificreports/   www.nature.com/scientificreports/ the hydrogen at the 2-position of the imidazolium ring. At the same time, pyridine activates nucleophiles by removing the acidic hydrogens from these compounds. The dual activation of nucleophiles and electrophiles by the imidazolium and pyridine is essential to promote the reaction in good to high yields. This activation effect can be clearly observed in the synthesis of 2-amino-3-cyano-4H-chromenes from the in-situ formed aldehydes containing electron-resealing or electron-withdrawing groups in good to high yields, regardless of the electron density of the substrates (Table 4, entries 1-10).
The probability of formation of dicyanoolefins (A) (Fig. 16) as an intermediate in the reaction was studied by performing the catalytic reaction of benzyl alcohol with malononitrile in the presence of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 under optimized reaction conditions (Fig. 17). 2-Benzylidenemalononitrile, was isolated in 93% yield (Table 8, entry 1) and characterized by its 1 H NMR spectrum (Supplementary Fig. S15). A reaction between 2-benzylidenemalononitrile and dimedone in the presence of catalyst was also conducted (Fig. 18) and 2-amino-3cyano-4H-chromene was isolated in 96% yield (Table 9, entry 1). These results clearly confirmed the formation of Knoevenagel condensation product (A), as an intermediate in the TOP synthesis of 2-amino-3-cyano-4Hchromenes from alcohols. Similar reactions in the presence of (γ-Fe 2 O 3 -Im-Me) 2 WO 4 as pyridine-free analogue of the catalyst produced the desired product in lower yield (Tables 8 and 9, entry 2), which showed the special role of pyridine as a base in the Knoevenagel and sequential Michael addition-cyclization reactions.   www.nature.com/scientificreports/ The catalyst recyclability and reusability were examined in the oxidation of benzyl alcohol and also in the preparation of functionalized 2-amino-3-cyano-4H-chromene via multicomponent TOP in the model reaction, under optimized reaction conditions. Ethyl acetate was added to the completed reaction and (γ-Fe 2 O 3 -Im-Py) 2 WO 4 was isolated simply using an external magnet, washed with EtOAc and EtOH. Then, the catalyst dried in a vacuum oven, and recycled again for another new batch. After five consecutive runs, the catalyst still showed high catalytic performance (Fig. 19). To demonstrate that (γ-Fe 2 O 3 -Im-Py) 2 WO 4 is truly heterogeneous, a leaching experiment was directed. Analysis of the reaction mixture by ICP after catalyst separation showed that the leaching was very low, so that after the 5 th recovery, the leaching amount of tungsten was less than 0.3 ppm. The result of ICP showed that (γ-Fe 2 O 3 -Im-Py) 2 WO 4 is truly heterogeneous and catalyst leaching is negligible under this reaction condition. FT-IR (Fig. 20a), VSM (Fig. 20b) and TEM images (Fig. 20c,d) of the recycled (γ-Fe 2 O 3 -Im-Py) 2 WO 4 after five runs also revealed the significant stability of the catalyst.
Considering the importance of large-scale reactions, in the last part, we have evaluated the scalability of the oxidation reaction and muticomponent TOP synthesis of 2-amino-3-cyano-4H-chromenes. To do this, the oxidaton reaction of benzyl alcohol and also muticomponent TOP of benzyl alcohol, malononitrile and dimedone in a scaled-up procedure (50 times) in the presence of (γ-Fe 2 O 3 -Im-Py) 2 WO 4 was carried out successfully under the optimized reaction conditions. Interestingly, the scaled-up reaction accompanied with 95 and 88% isolated yields of the desired products.

Conclusion
In this study, we have designed and synthesized a novel base-metal multifunctional catalyst [(γ-Fe 2 O 3 -Im-Py) 2 WO 4 ]. This multifunctional heterogeneous nanocatalyst is completely characterized by various techniques such as FT-IR, XPS, TEM, FESEM, ICP, TGA, VSM and XRD. Then, its catalytic activity was evaluated in the synthesis of 2-amino-3-cyano-4H-chromenes via a multicomponent tandem oxidation process starting from alcohols as suitable alternatives for integrate consideration of economic viability and environmental integrity. Different types of 2-amino-3-cyano-4H-chromenes were produced in good to high yields by the reaction of different types of in-situ formed aldehydes with malononitrile, and β-dicarbonyl compounds/naphthols/4-hydroxycumarin under solvent-free conditions. The catalyst operated by a dual activation of nucleophiles and electrophiles and was readily separated from the reaction mixture and reused in five cycles with high degree of efficiency. The high efficiency of the catalyst is related to the tandem catalytic effect of tungstate in the oxidation of alcohols and the basic role of pyridine and imidazolium sites in the Knoevenagel condensation-Michael addition-cyclization reaction of in-situ formed aldehydes with malononitrile and activated nucleophilic components. www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.