Synthesis of triarylpyridines with sulfonate and sulfonamide moieties via a cooperative vinylogous anomeric-based oxidation

Herein, novel magnetic nanoparticles with pyridinium bridges namely Fe3O4@SiO2@PCLH-TFA through a multi-step pathway were designed and synthesized. The desired catalyst and its corresponding precursors were characterized with different techniques such as Fourier transform infrared (FT-IR) spectroscopy, 1H NMR, 13C NMR, Mass spectroscopy, energy dispersive X-ray (EDX) analysis, thermogravimetric/derivative thermogravimetry (TG/DTG) analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and vibrating sample magnetometer (VSM). In addition, the catalytic application of the prepared catalyst in the synthesis of new series of triarylpyridines bearing sulfonate and sulfonamide moieties via a cooperative vinylogous anomeric-based oxidation was highlighted. The current trend revealed that the mentioned catalyst shows high recoverability in the reported synthesis.

www.nature.com/scientificreports/ In addition to the critical role of anomeric effect for the explanation of unusual observations in structure and reactivity of oxygen-containing molecules [81][82][83][84][85] , this important stereoelectronic effect demonstrates itself as a powerful phenomenon for justifying the weird results in various heteroatom-rich compounds such as hydrazine and tetrafluorohydrazine [86][87][88][89] . In the case of hydrazine, the gauche-conformer is more stable than the anticonformer. This observation originates from the stabilizing anomeric interactions of lone pair electrons of the nitrogen atom with a vacant antibonding orbital of adjacent N-H bond (n N → σ* N-H ). These interactions are not possible in anti-conformer (Scheme 2). On the other hand, in the case of tetrafluorohydrazine the anti-conformer is more stable than the gauche conformation due to homoanomeric interactions. In the anti-conformer, instead of n N → σ* N-F interactions, four n F → σ* N-F homoanomeric interactions are operative and control the stability of conformers (Scheme 3) 90 .
In the vinylogous anomeric effect, as an important subclass of anomeric effect, electron transfer interactions occurred through C = C bonds. This phenomenon has attracted the attention of many researchers [91][92][93][94][95][96][97][98][99] . Vinylogous anomeric effect can control the chemical reactivity. For example, Ferrier rearrangement facilitated when the leaving group exists at pseudo-axial position. In this position vinylogous anomeric effect is on and the reaction promoted by n O -π C=C → σ* C-O interaction (Scheme 4) 100 .
Herein, we pursue our previous works for the synthesis of pyridines [101][102][103][104][105][106][107] and reported the synthesis and catalytic performance of a novel pyridinium tagged magnetic nanoparticles namely Fe 3 O 4 @SiO 2 @PCLH-TFA, for the synthesis of the new library of triarylpyridines bearing sulfonate and sulfonamide moieties via a cooperative vinylogous anomeric-based oxidation mechanism [108][109][110][111][112] (Schemes 5,6). We believe that the co-existence of pyridine moiety and sulfonate or sulfonamide segment within the structure of a single molecule has a significant impact on the biological importance of these versatile structures.

Results and discussion
Since that the pyridines with sulfonate and sulfonamide moieties have been considered as drug candidates, the synthesis of a new library of symmetrical triarylpyridines bearing sulfonate and sulfonamide moieties are our main research interest. Therefore, herein we wish to present a new catalytic system with pyridinium linkers for the synthesis of the above-mentioned compounds. According to Alabugin's theory, which has introduced stereoelectronic effects as a bridge between structure and reactivity [86][87][88][89] , we have also applied the above-mentioned theory in the course of the reaction mechanism.
FT-IR spectrum of Fe 3 O 4 @SiO 2 @PCLH-TFA and related intermediates including Fe 3 O 4 , Fe 3 O 4 @SiO 2 , PCL and Fe 3 O 4 @SiO 2 @PCL were discussed in a comparative investigation. The changes made in each of the intermediates confirm their proper synthesis, which finally confirms the successful preparation of Fe 3 O 4 @SiO 2 @PCL. www.nature.com/scientificreports/ carbonyl groups related to the structure of the prepared catalyst appeared at around 1687 cm −1 as a broad peak.
In the structure of desired catalyst, the broad peak at about 2500-3500 cm −1 is related to pyridinium moiety, amidic NH groups of the PCL and free hydroxyl groups of the Fe 3 O 4 @SiO 2 @PCLH-TFA (Fig. 1). The elemental composition of Fe 3 O 4 @SiO 2 @PCLH-TFA was characterized using energy-dispersive X-ray spectroscopy (EDX). According to the outcome data, all expected elements including iron, silicon, oxygen, carbon, nitrogen and fluorine were approved (Fig. 2). Furthermore, to confirm this observation, elemental mapping analysis was investigated (Fig. 3). The elemental mapping reveals uniform distribution of the mentioned elements.
For a better description of catalyst, the surface and morphology property analysis of Fe 3 O 4 @SiO 2 @PCLH-TFA was also studied by SEM images. According to the SEM images the morphology of the catalyst is spherical (Fig. 4). But by more focusing, it can be seen that each sphere is made from the aggregate of smaller size nanoparticles. For further clarification, the TEM images were recorded (Fig. 5) and it clearly shows that the bigger particles are made from nanopraticles (4-6 nm) and with core-shell structure. The TEM results confirmed the obtained data from SEM images (Fig. 5).
TG has been generally applied to evaluate thermal degradation behaviour of magnetic nanoparticles. To determine the thermal behaviour of the Fe 3 O 4 @SiO 2 @PCLH-TFA, TG/DTG was carried out. The obtained results are illustrated in Fig. 6 and show good thermal stability for the prepared Fe 3 O 4 @SiO 2 @PCLH-TFA.
The VSM analysis was employed to determine magnetic properties of Fe 3 O 4 @SiO 2 @PCLH-TFA in comparison with its related precursors such as Fe 3 O 4 and Fe 3 O 4 @SiO 2 . Decreasing the magnetic property of Fe 3 O 4 @SiO 2 @ PCLH-TFA compared to its precursors, indicates the successful addition of organic moieties onto the surface  www.nature.com/scientificreports/ of magnetic precursor (Fig. 7). The value of magnetic saturation of Fe 3 O 4 @SiO 2 @PCLH-TFA is about 25 emu/g which is enough for its easy separation from the reaction mixture upon completion of the catalytic reaction. After targeted and multi-step synthesis and characterization of Fe 3 O 4 @SiO 2 @PCLH-TFA as a novel pyridinium tagged magnetic nanoparticles, we evaluated its catalytic performance for the synthesis of a new library of triarylpyridines bearing sulfonate and sulfonamide moieties via a cooperative vinylogous anomeric-based oxidation mechanism. For this purpose, we designed a model reaction for achieving the best operational reaction conditions. In this regard, the reaction of 4-choloro benzaldehyde, 4-acetylphenyl-4-methylbenzenesulfonate and ammonium acetate was selected and the role of solvents, temperature and amount of Fe 3 O 4 @SiO 2 @PCLH-TFA as catalyst was investigated. Based on resulted experimental data, the utilization of 10 mg of Fe 3 O 4 @SiO 2 @ PCLH-TFA at 110 °C under solvent-free conditions is the best conditions for the synthesis of target molecules 1f. from time and yield perspective ( Table 1). www.nature.com/scientificreports/ Also, we tested the model reaction (synthesis of molecule 1f.) in the presence of related intermediates of Fe 3 O 4 @SiO 2 @PCL and some known catalysts to validate the importance of the existence of ionic tag (pyridinium site) within the structure of Fe 3 O 4 @SiO 2 @PCLH-TFA as the catalyst. As inserted in Table 2, the novel synthesized catalyst shows the best results in comparison with some other catalysts and verified the crucial role of the acidic and hydrogen-bond sites within the structure of the catalyst.
In another study with considering the above-mentioned encouraging results under optimal reaction conditions, we generalized a catalytic procedure for the synthesis of a new library of triarylpyridines bearing sulfonate and sulfonamide moieties using Fe 3 O 4 @SiO 2 @PCLH-TFA as a novel recoverable catalyst. In this synthetic procedure, different ketones with sulfonate and sulfonamide moieties and various aromatic aldehydes bearing electron-withdrawing and electron-releasing substituents were utilized. Also, terephthaldehyde revealed promising results. The collected data are inserted in Table 3.
Also, a plausible mechanism for the synthesis of 2c (Scheme 7) is suggested. At the first, 4-acetylphenyl-4-methylbenzenesulfonate was activated by Fe 3 O 4 @SiO 2 @PCLH-TFA, and converted to its corresponding enolic form. Then the mentioned enolic form was reacted with activated benzaldehyde with catalyst. This reaction leads to the formation of chalcone intermediate A. Then, intermediate A undergoes a nucleophilic attack from the enolic form of 4-acetylphenyl-4-methylbenzenesulfonate which resulted in the formation of intermediate B.
In the next step, ammonia derived from the dissociation of ammonium acetate attacked to intermediate B and enamine C is produced. After this, through a sequential reaction including, a tautomerization process, intramolecular nucleophilic attack and dehydration, intermediate C converted to intermediate E. Finally, releasing of molecular H 2 is facilitated based on a cooperative vinylogous anomeric-based oxidation (CVABO) in intermediate E which leads to the formation of the desired molecule after deprotonation of intermediate F.
Considering the high potential of magnetic catalysts in recovering and reusing processes, we investigated the recovering and reusing of Fe 3 O 4 @SiO 2 @PCLH-TFA in a model reaction for the synthesis of target molecule 1f. under optimal reaction conditions (Fig. 8). After completing each run of reaction, the catalyst was separated from the mixture of reaction using an external magnet. Then, the separated catalyst was washed several times  www.nature.com/scientificreports/ with ethanol and dried. This process was performed seven times without significant reduction in the reaction efficiency. Finally, the stability of the catalyst was confirmed by comparison of FT-IR spectra of recovered and fresh catalyst (See ESI). In a separate study, the reaction kinetics was investigated by UV-visible spectroscopy upon the model reaction for the synthesis of molecule 1f. For this purpose, the UV-visible spectrum of reaction components was recorded as a function of time. At different time intervals, a sample of the reaction mixture was dissolved in ethanol and its spectrum was recorded with a UV-visible spectrophotometer. The obtained spectrums at different time intervals were presented in Fig. 9a. The peak centered at 250 nm doesn't show any regular variation because of the overlapping of reactants, intermediates, and products peaks. But the peak centered at about 210 nm, decreases with time, as shown by an arrow. This peak belongs to reactants since decreases with reaction time. The plot of normalized absorbance (A/A 0 ) at λ max = 210 nm versus time is shown in Fig. 9b. This plot clearly shows non-linear decrease of absorbance versus time. The slope of this plot (rate of reaction) at t < 20 min is higher than its slope at t > 20 min, indicating higher rate of reaction at the first 20 min of reaction. At a longer time, the rate of reaction decreases.   www.nature.com/scientificreports/ Also, in another investigation and similar to the synthetic protocol of PCL, we tried to use (I) directly for the preparation of a new dihydropyridine containing ligand (DHPCL) as a reductant reagent such as biological NADH2/NAD + systems which capable to be heterogeneous. For this goal, (I) and hydrazine hydrate subjected to the reaction under refluxing EtOH. Our prediction was the production of molecule (IV). The achieved NMR www.nature.com/scientificreports/ data (see ESI) did not match the expected structure (IV). Initial interpretations of the obtained NMR data were apparently in accordance with a molecular cage (V). So, with this hypothesis, we applied X-ray crystallography to determine the exact structure. Surprisingly, based on the results of X-ray crystallography, it is revealed that 4,4′-methylenebis(5-methyl-1H-pyrazol-3-ol) (VI) has been formed (Scheme 8 and Fig. 10)

Experimental section
General. All materials and reagents were purchased from Merck and Sigma-Aldrich companies and were used without further purification. Double distilled water was used in all reactions. 1 H NMR spectra were recorded on a Bruker spectrometer operating at 300 MHz, and 13 C NMR spectra were recorded on a Bruker spectrometer operating at 75 MHz. TEM analysis was performed with an instrument model EM10C-100 kV from ZEISS. SEM analysis was performed with SIGMA VP instrument from ZEISS. The instrument of EDX-Mapping analysis is related to Oxford Instruments company. TGA/DTG analysis was performed under nitrogen conditions applying STA-1500 instrument from Rheometric Scientific. The magnetic properties of the catalyst were investigated with VSM analysis that was performed using LBKFB instrument from Meghnatis Daghigh Kavir Company. XRD analysis was performed with X' Pert Pro instrument from Panalytical. A UV-visible spectrophotometer (PG-Instrument-T80) was applied for the study of reaction kinetics.
General procedure for the synthesis of PCL. PCL was synthesized by the reaction of triethoxy(3-isocyanatopropyl) silane (5 mmol, 1.237 g) and III (12 mmol, 2.68 g) under neat conditions at room temperature for 24 h.  www.nature.com/scientificreports/ of Fe 3 O 4 @SiO 2 @PCLH-TFA as catalyst were added. Then, the reaction mixture was stirred under solvent-free conditions at 110 °C for requisite times ( Table 3). The progress of the reaction was inspected by TLC techniques (n-hexane/ethylacetate as eluent). After completion of each reaction, the reaction mixture was dissolved in hot ethanol and the insoluble nanomagnetic catalyst was isolated from the reaction mixture by using an external magnet. Then, target molecules were purified by TLC plate with n-hexane/ethyl acetate as eluent.

Conclusion
In this work, Fe 3 O 4 @SiO 2 @PCLH-TFA as a novel magnetic nanoparticle with pyridinium bridges was designed, synthesized and characterized with FT-IR, EDX, XRD, SEM, TEM, TG/DTG and VSM. Then, Fe 3 O 4 @SiO 2 @ PCLH-TFA was applied in the multicomponent synthesis of a new library of triarylpyridines bearing sulfonate and sulfonamide moieties via a cooperative vinylogous anomeric-based oxidation. According to the obtained results, the reactions were performed under mild conditions and short reaction time, and the synthesis of