Green synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazoles] using Fe3O4@l-arginine as a robust and reusable catalyst

The synthesized Fe3O4@l-arginine showed strong catalytic performance in the one-pot synthesis of spiropyranopyrazoles via the reactions of hydrazines, β-keto esters, isatins, and malononitrile or ethyl cyanoacetate under solvent-free conditions. The biologically active heterocyclic compounds including spiropyranopyrazole derivatives were efficiently synthesized in short reaction times and excellent yields in the presence of Fe3O4/l-arginine at room temperature. The highlighted features of the Fe3O4@l-arginine nanocomposite are highly stable, easy to separate, low loading, cost-effective with easy preparation and reusability of the catalyst. The heterogeneous nanocomposite was fully characterized by SEM, EDX, FT-IR, XRD and TEM analysis.


Introduction
One-pot multi-component reactions (MCRs), is an interesting synthetic strategy for the synthesis of small-molecule libraries with various degrees of structural variety because various organic moieties are joined in one step for carbon-carbon and carbon-heteroatom bond formation [1,2]. They offer considerable advantages over ordinary linear step synthesis by decreasing time, saving money, energy, and crude materials. Therefore, they result in both economical and environmental benefits. At the same time, variety can be gained from building up libraries by differing each component [3,4]. In recent years, there has been massive development in three-and four-component reactions, and great efforts continue to be made to expand new MCRs [5]. Spirocyclic compounds are considered as significant building canton for the easy availability of a diversity of cyclic products by a sequential reaction due to their steric strain attendant with the quaternary carbon [6]. Expansion of new procedures for producing spirocyclic compounds is an interesting and challenging function in organic synthesis [7]. One of the significant multi-component reactions is the synthesis of spiropyranopyrazole derivatives which exhibit high medicinal attributes and biological activities. Spiropyranopyrazoles area class of nitrogen heterocyclic compounds with considerable and well-offered biological activities that consist of antimicrobial [8], anti-inflammatory [9], anticancer [10] and molluscicidal activities [11]. Spiropyranopyrazoles are important heterocyclic compounds due to their variety and pharmaceutical biological activities [12]. Concerning the arithmetic of the significance of oxindole parts in organic compounds, as well as the intrinsic complexity of isatins as heterocyclic substrates, it is not amazing that many diverse and elegant MCRs have been introduced for the synthesis of various heterocyclic and spiroheterocyclic products by using isatins as a core component [13]. Therefore, different synthetic approaches for the synthesis of spirooxindole-fused heterocycles have been reported and reviewed [14]. Previous studies have described procedures to synthesize of pyrano [2,3-c]pyrazoles using several catalysts such as cerium ammonium nitrate [15], l-proline [16], piperidine [17] and cobalt NPs [18].
Nevertheless, there are only two reported methods in the literature for the synthesis of spiro[indoline-3,4′pyrano [2,3-c]pyrazole] derivatives via four-component reaction of hydrazines, ethyl acetoacetate, isatins, and malononitrile or ethyl cyanoacetate which have been done in the presence of piperidine [19], and Et 3 N [20].
Magnetic organic-inorganic nanocomposites have recently been the subject of intense research as magnetic catalysts in both industrial and academic settings. These magnetic nanoparticle catalysts can be used for investigating the reusing and seclusion problems that occur in several homogenous and heterogeneous catalytic reactions. Supported magnetic metal nanoparticles as new class of nanocatalysts have received much attention in diverse fields. The main feature of these particles is their high surface area that leads to their higher catalytic activity in comparison with traditional heterogeneous acid catalysts [21][22][23][24][25][26][27].
One of the outstanding procedures for preventing particle aggregation is coating nanoparticles with various targeting factors, taking into account their biocompatibility. Among the chemicals that can be used for achieving this target, amino acids are appropriate because of their crucial role in the body [28]. Amino acids react with the nanoparticles' surface via the carboxyl groups and side chains [29]. Amino-functionalized materials demonstrate excellent ability to remove an extensive range of heavy metal ions from aqueous solutions because of the potent affinity between the nitrogen atom and metal cations [30]. Among different nanocomposite, Fe 3 O 4 / amino acid has received great attention in different fields because of their unique attributes and potential functions [31]. Some crucial characteristics of these catalysts include high catalytic activity, facile separation through an external magnet with no need for filtration, ecofriendliness, and non-toxicity. Recently, functionalized magnetic nanoparticles have been utilized as a useful catalytic system in numerous chemical processes such as synthesis of α-amino nitriles [32], bis(indolyl)methane derivatives [33], indazolo [2,1-b]phthalazine-triones and pyrazolo [1,2-b]phthalazine-diones [34], 3,4-dihydropyrimidin-2(1H)-ones [35], 1,8-dioxo-octa hydro xanthene derivatives [36], 2-amino-4H-chromen-4-yl phosphonates [37], 1,4-dihydropyridines [38] and pyrrole synthesis [39].

Catalyst characterization
In the preliminary experiments Fe 3 O 4 @l-arginine nanoparticles were prepared and characterized by SEM, EDX, FT-IR and XRD spectroscopy tenchniques.
The chemical purity of the sample, as well as their stoichiometry, was tested by EDX study. Figure     nanoparticles. Furthermore, the connections and interactions between COO − groups and metal atoms are completely according to pervious literature [45][46][47][48].
In order to investigate the morphology and particle size of nanoparticles, SEM image of the mesoporous is illustrated in Fig. 5. The SEM image of the magnetite nanoparticles modified with arginine indicate spherical shape with an average diameter about 10-15 nm.
The morphology and particle size of Fe 3 O 4 @l-arginine were investigated using transmission electron microscopy (TEM) (Fig. 6). The TEM image of this nanocomposite shows that the average particle size of Fe 3 O 4 @l-arginine is around 10-20 nm which was confirmed by the SEM image.

Discussions
Initially, to obtain the best reaction conditions, we selected reaction of hydrazine, ethyl acetoacetate, isatin and malononitrile as model reaction. Different  (Fig. 7). Firstly, the model study was performed in various solvents including EtOH, DMF, H 2 O, CH 3 CN and PhCH 3 under reflux conditions and also under solvent-free conditions using Fe 3 O 4 @l-arginine nanocomposite. The summarized results of Table 1 show that the best results were obtained under solvent-free conditions. To further improve the yield and decrease the reaction time, we used the different reaction temperatures under solventfree conditions. Further increase in temperature from room temperature to 80 °C in the model study did not have any remarkable influence on the reaction time and production yield (Table 1). Afterward, the model was performed using several catalysts including ZnO, CuI, MgO, Na 2 CO 3 , Et 3 N, piperidine, Fe 3 O 4 , CaO, SiO 2 , and Fe 3 O 4 @l-arginine under solventfree conditions. As can be seen from Table 2, no product was afforded in the absence of a catalyst ( Table 2, entry  1). Also, it is noticed that Fe 3 O 4 @l-arginine has a significant effect in the yield of the corresponding product and reaction time (Table 2, entry 11). Next, various amounts of the Fe 3 O 4 @l-arginine were used in the model reaction. As shown in Table 2, the best experimental operation conditions included 8 mol % of the Fe 3 O 4 @l-arginine. With increasing the amount of nanocatalyst, no considerable change was observed in the product yield and reaction time. In comparison, a decrease in the catalyst amount cause to decrease the product yield. Hence, 8 mol % Fe 3 O 4 @l-arginine was selected as the optimum amount in the model reaction ( Table 2).
The corresponding spiro-[indoline-3,4′-pyrano [2,3-c] pyrazole] derivatives 5 were obtained in good yields at room temperature under solvent-free conditions ( Table 3). The protocol was effective with isatins containing either electron-withdrawing (halides) or electrondonating (alkyl) groups.     The model study was run several times using recycled magnetic nanocomposite to consider the recoverability level and lifetime of the Fe 3 O 4 @l-arginine nanocomposite. The results showed that the recovered magnetic nanocomposite can be utilized for five successive runs with a negligible decrease in its activity (Table 4).
A possible mechanism for the synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazoles] using Fe 3 O 4 @l-arginine MNPs is presented in Fig. 10. This mechanism is based on the results of our experiment and some literature [19]. According to this mechanism, a condensation of hydrazine 1 with β-keto esters 2 is offered to give the intermediate A.

Conclusions
In conclusion, we have demonstrated that Fe 3 O 4 @l-arginine nanocomposite is an effective catalyst for the MCRs of hydrazine, β-keto esters, isatins, and malononitrile or ethyl cyanoacetate under solventfree conditions at room temperature. The heterocyclic compounds including spiro[indoline-3,4′-pyrano [2,3-c] pyrazole] derivatives were obtained in high yields. The catalyst can be recovered and reused at least up to five runs for the synthesis of corresponding product. The one-pot nature and the use of heterogeneous solid Brønsted basic catalyst as an eco-friendly structure make it an interesting alternative to multi-step approaches.

Chemicals and apparatus
Chemicals were purchased from the Sigma-Aldrich and Merck in high purity. All of the materials were of commercial reagent grade and were used without further purification. The synthesis and characterization of the studied compounds were previously reported [49]. Melting points of products were determined by Electro thermal 9200. 1 H NMR and 13 C NMR spectra were obtained on Bruker 400 MHz spectrometer with DMSO-d 6 as solvent using TMS as an internal standard. FT-IR spectrum was recorded on Magna-IR, spectrometer 550. The elemental analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer. Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer of X'pert Company with mono chromatized Cu Kα radiation (λ = 1.5406 Å). Microscopic morphology of products was visualized by SEM (LEO 1455VP). The compositional analysis was done by energy dispersive analysis of X-ray (EDX, Kevex, Delta Class I). Transmission electron microscopy (TEM) was performed with a Jeol JEM-2100UHR, operated at 200 kV.