Design, preparation and application of the semicarbazide-pyridoyl-sulfonic acid-based nanocatalyst for the synthesis of pyranopyrazoles

A novel, efficient, and recoverable nanomagnetic catalyst bearing the semicarbazide linkers, namely, Fe3O4@SiO2@OSi(CH2)3-N(3-pyridoyl sulfonic acid)semicarbazide (FSiPSS) was designed, synthesized and characterized by the use of various techniques such as FT‐IR, EDX, elemental mapping analysis, XRD, SEM, TEM, TGA/DTA, BET, and VSM. Then, the catalytic capability of the novel prepared nanomagnetic FSiPSS catalyst was successfully investigated in the synthesis of diverse pyranopyrazoles through a one-pot four-component condensation reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes, and malononitrile or ethyl cyano-acetate by the help of ultrasonication in very short reaction time, good to high yields and easy work-up (Fig. 1).Figure 1 Synthesis of diverse pyranopyrazoles by the FSiPSS nano-catalyst.

. Synthesis of diverse pyranopyrazoles by the FSiPSS nano-catalyst.   www.nature.com/scientificreports/ Then, the FSiPSS nano-catalyst was used as an efficient heterogeneous catalyst for the synthesis of pyranopyrazoles via a one-pot four-component condensation reaction of ethyl acetoacetate 1, hydrazine hydrate 2, aromatic aldehydes 3, and malononitrile or ethyl-cyano-acetate 4 under ultrasonic conditions (Fig. 3).

Experimental
General. All the commercial reagents were obtained from the Merck or Aldrich chemical companies and used without further purification. The reaction progress and purity of the synthesized compounds were monitored by TLC performed with silica gel 60 F-254 plates. FT-IR spectra were recorded on a PerkinElmer Spectrum Version 10.02.00 using KBr pellets. The 1 H NMR (250 MHz) and 13 C NMR (62.5 MHz) spectra were recorded on a Bruker spectrometer (δ in ppm) using DMSO-d 6 as a solvent with chemical shifts measured relative to TMS as the internal standard. Melting points were taken with a BUCHI 510 melting point apparatus. Elemental analysis was done using a MIRA II analyzer. The TEM images were recorded on a CM120 total carbon analyzer. The FESEM images were recorded using a MIRA III analyzer. The X-ray diffraction (XRD) measurements were performed with an XRD Philips PW1730. Thermogravimetric-differential thermal analysis (TG-DTA) was carried out using an SDT-Q600 device. A 2200 ETH-SONICA ultrasound cleaner (50 Hz) was employed for ultrasonication purposes.
General procedure for the construction of Fe 3 O 4 @SiO 2 @OSi(CH 2 ) 3 -N(3-pyridoyl sulfonic acid) semicarbazide (FSiPSS). The FSiPSS nano-catalyst was prepared in the following four consecutive stages:      www.nature.com/scientificreports/ the reaction, the FSiPSS nano-catalyst was separated by a super magnet, the pure products obtained by recrystallization in ethanol and characterized by FT-IR, NMR, and mass spectrometry techniques.

Results and discussion
The  Table 1.

Characterization of the FSiPSS nanocatalyst by VSM.
In another study, VSM analysis was performed for the exploration of the magnetic behavior of the FSiPSS nano-catalyst (D) and the corresponding compounds (A, B, C). As illustrated in Fig. 7, decrease saturation magnetization from about 70 emu g −1 (for major core Fe 3 O 4 ) to about 10 emu g −1 for the FSiPSS nano-catalyst is related to the newly coated layer which can be explained by the reduction in the dipole-dipole interactions between the magnetic nanoparticles after their coating with SiO 2 and functionalization with ligand A and chlorosulfonic acid.
Characterization of the FSiPSS nano-catalyst by the SEM. To study the particle size and surface morphology of the newly prepared catalyst, SEM images were also taken. The resulting images are exposed in Fig. 8. According to these images, the sizes of the FSiPSS nano-catalyst particles are in the nanometer ranges (between 13.66 and 35.86 nm).

Characterization of the FSiPSS nano-catalyst by the TEM images. The obtained TEM images also
proved that the sizes of the FSiPSS nano-catalyst particles are in the nanometer ranges, as shown in Fig. 9. Moreover, the core-shell structure of the nano-catalyst can be apperceived through TEM images. At a closer investigation, as illustrated in the particle size distribution histograms (Fig. 10), the sizes of the nanoparticles are between 5 and 20 nm, and the average particle size is evaluated at about 9.61 nm.  applied to investigate the thermal behavior of the FSiPSS nano-catalyst. The obtained curve is presented in Fig. 11. The thermo-gravimetric curve displays the three mass losses upon heating. The weight loss from about 60-120 °C (23%) can be attributed to the loss of water molecules, the weight loss from 120 to 300 °C (7%) can be related to the decomposition of acidic functional groups and the weight loss from 300 to 650 °C (17%) can be attributed to the decomposition of the ligand A. Also, about 72% of the initial mass remains at 700 °C.    56 . The   www.nature.com/scientificreports/ obtained pattern is in good agreement with the characteristic peaks of bare Fe 3 O 4 which indicates the retention of the crystalline spinel ferrite core structure during the functionalization of MNPs and the successful synthesis of desired catalyst 57 . In addition, the successful synthesis of Fe 3 O 4 @SiO 2 core-shell was confirmed by the presence of a broad peak at 2θ = 20°-30° which is due to the amorphous silicon layer, demonstrating that the magnetic moiety structure was protected in the core where SiO 2 cover did not alter the crystal structure of the magnetic Fe 3 O 4 nanoparticles 58 . In addition, after anchoring the OSi(CH 2 ) 3 -N(3-pyridoyl sulfonic acid)semicarbazide functional groups, the peaks were found to have background noise levels increased, that coming from the amorphous added sulfonic acid functionalities 59  Characterization of the FSiPSS nano-catalyst by BET. The specific surface area of the synthesized catalyst was determined by the N 2 adsorption-desorption analysis. The specific surface area, the total pore volumes (V total), the pore diameters (DBJH), and the wall thickness of the samples were inspected at 77 Kelvin for 6 h. The results indicate that according to the IUPAC classification of adsorption isotherms 60 , the N 2 isotherm resembles the type III (Fig. 13). The obtained results of BET measurements were represented in Table 2. According to the obtained data, the surface area of the catalyst is 35.6 m 2 g −1 , which can provide a sufficient surface area for the catalyst to perform the desired synthesis.    Optimization of the reaction conditions. After synthesis and full characterization of the novel FSiPSS nano-catalyst, the catalytic performance of the prepared nanomagnetic catalyst was also evaluated in the synthesis of pyranopyrazole derivatives. To attain this target, the reaction of ethyl acetoacetate, hydrazine hydrate, malononitrile, and benzaldehyde in the presence of the FSiPSS nano-catalyst was selected as a model reaction to find the best reaction conditions. The resulting data in various temperatures, amounts of the catalyst, and solvents are outlined in Table 3. The obtained data indicate that the best results were achieved when the reaction is carried out in the presence of 20 mg of the FSiPSS nano-catalyst in ethanol at 40 °C under ultrasonic conditions   www.nature.com/scientificreports/ (entry 2). In addition, the effect of ultrasonication was also studied and its significance can be observed in time of the reaction which is drastically reduced as demonstrated in Tables 3 and 4. On other hand, the role of each part of the catalyst in the reaction was also investigated which the last step is the most effective according to entry 7 of Table 4.

Synthesis of diverse pyranopyrazoles 5(a-n).
In the next step, with optimal reaction conditions in hand, the scope and generality of the presented method were investigated by examining the reaction of ethyl acetoacetate 1, hydrazine hydrate 2, various aromatic aldehydes 3(a-n), and malononitrile 4a or ethyl cyanoacetate 4b in the presence of the catalytic amount of the FSiPSS nano-catalyst under ultrasonic conditions (Table 5). Fig. 15. According to our suggested mechanism, firstly, a nucleophilic attack   Fig. 16. Subsequently, an intramolecular nucleophilic attack of the oxygen of the carbonyl group to the cyano group gives the desired pyrazole 5o.  www.nature.com/scientificreports/ Reusability of the FSiPSS nano-catalyst. In a separate study, recyclability and reusability of the magnetic FSiPSS nano-catalyst were tested for the synthesis of target molecule 5a under optimal reaction conditions.  www.nature.com/scientificreports/ At the end of each run, the magnetic FSiPSS nano-catalyst is separated from the reaction mixture by using a simple external magnet, washed thoroughly with EtOH, dried, and reused for the next run. Figure 17 demonstrates that the catalyst activity is preserved after four successive cycles without any considerable decrease in yield and reaction time.

Synthesis of ethyl 4-benzyl-5-imino-3-methyl-4,5-dihydro-1H-furo[2,3-c]pyrazole-4-carbox
Comparison of the catalyst activities. In addition, the efficiency of our proposed protocol was also evaluated comparatively with some previously reported methods for the synthesis of pyranopyrazoles. According to Table 6, our proposed protocol used in this paper for the synthesis of pyranopyrazoles has no disadvantages and is accessible, applicable, and reusable with a very short reaction time, good for high yields and easy work-up.

Conclusion
In summary, the synthesis of pyranopyrazole derivatives was performed using a sulfonic acid-functionalized nanomagnetic catalyst bearing the semicarbazide linkers as a new high-performance catalytic system under ultrasonic conditions. The simple and easy manufacturing procedure of this catalyst, along with the ability to recover and reuse it, makes it economical. The most attractive features of this procedure are low catalyst loading, short reaction times, good to high yields, lower temperature rather than previous works, compatibility with various functional groups, easy work-up, facile separation, and recyclability of catalyst.
Regarding the limitations of this project, the following points can be mentioned: • Yield of the reaction: The yield of the reaction is between 40 and 80%, which can be improved in future by performing the reaction under new optimized conditions to increase the yield of the products.   Figure 16. The proposed mechanism for the synthesis of the desired pyrazole 5o.  (1) TEA-Im-IL-Cu, rt, 65 min, 80% 30 (2) Isonicotinic acid (10 mol%), solvent-free, 85 °C, 10 min, 90% 32 (3) TrCl (10 mol%), solvent-free, 60