Application of novel nanomagnetic metal–organic frameworks as a catalyst for the synthesis of new pyridines and 1,4-dihydropyridines via a cooperative vinylogous anomeric based oxidation

Herein, a new magnetic metal–organic frameworks based on Fe3O4 (NMMOFs) with porous and high surface area materials were synthesized. Then, NMMOFs were characterized by FT-IR, XRD, SEM, elemental mapping, energy dispersive X-ray (EDS), TG, DTG, VSM, and N2 adsorption–desorption isotherms (BET). Fe3O4@Co(BDC)-NH2 as a magnetic porous catalyst was applied for synthesis of novel fused pyridines and 1,4-dihydropyridines with pyrazole and pyrimidine moieties as suitable drug candidates under ultrasonic irradiation. The significant advantages of the presented methodology are mild, facile workup, high yields, short reaction times, high thermal stability, and reusability of the described NMMOFs catalyst.

www.nature.com/scientificreports/ Synthesis of composites of MOF and nano-magnetic Fe 3 O 4 is our great research interest. With this aim, we have decided to synthesize nano-magnetic metal-organic frameworks Fe 3 O 4 @Co(BDC)-NH 2 as a porous and magnetic catalyst under ultrasonic irradiation condition. This nanomagnetic metal-organic frameworks (NMMOFs) was applied in the synthesis of novel fused pyridines and 1,4-dihydropyridines with pyrazole and pyrimidine moieties by using the corresponding precursors in DMF (5 mL) as solvent under ultrasonic irradiation (Scheme 1). www.nature.com/scientificreports/ Experimental Materials and methods. All chemicals were purchased from Merck Chemical Company. The known products were identified by comparison of their melting points and spectral data with those reported in the literature. To scrutinize the progress of the reaction silica gel SIL G/UV 254 plates were used. From the model of the BRUKER Ultra shield, NMR spectrometer (δ in ppm) was recorded 1 H NMR (400 MHz) and 13 C NMR (100 MHz). Recorded on a Büchi B-545 apparatus in open capillary tubes were melting points. The PerkinElmer PE-1600-FTIR device was registered for the infrared spectra of compounds. SEM was performed using a scanning electron microscope for field publishing made by TE-SCAN. Thermal gravimetry (TG), differential thermal gravimetric (DTG) and differential thermal (DTA) were analyzed by a Perkin Elmer (Model: Pyris 1). The analysis 25-1000 °C, temperature increase rate of 10 °C min −1 .

Result and discussion
The systematic study of the stereoelectronic effects in target molecules, allows for the design of synthetic strategies based on a nomerically driven stereoselective reactions, or highly biased equilibria among isomeric products. To the best of our knowledge, many biological processes involve the oxidation-reduction of substrates by NAD + / NADH, respectively [37][38][39][40][41] . The key feature of the oxidation mechanism is hydride transfer from carbon via stereoelectronic interactions. Thus the development of stereoelectronic effects leads to knowledge-based designing www.nature.com/scientificreports/ of biomimetic reactions. The obtained results from this research will be supporting the idea of rational designs, syntheses, and applications of tasked-specific catalysts and molecules for the development of stereoelectronic effects in the course of organic synthesis. With this aim, a nanomagnetic metal-organic frameworks (NMMOFs) was designed, characterized and applied for the preparation of pyridines fused with pyrazole and pyrimidine under ultrasonic irradiation. At first, nanomagnetic metal-organic frameworks (NMMOFs) were synthesized (Scheme 2). Its schematic synthesis is showed in Fig. 2 (Table S1 see in supporting information) 43,44 .
For comparison, structure and elementals in the synthesis of step by step Fe 3 O 4 @CH 2 CO 2 H and Fe 3 O 4 @ Co(BDC)-NH 2 were also studied with energy dispersive X-ray analysis (EDX) analysis ( Figure S2 see supporting information). The structures of Fe 3 O 4 @Co(BDC)-NH 2 and Fe 3 O 4 @CH 2 CO 2 H were verified with existence of Fe, Co, N, C, O and Fe, C, O, and S atoms respectively 45 . Then, elementals dispersed over the surface of the catalyst, and step Fe 3 O 4 @Co(BDC)-NH 2 was checked out by SEM-elemental mapping ( Figure S3 see supporting information). The images in Figure S3 shows that all kinds of elements are well dispersed over the surface of Fe 3 O 4 @Co(BDC)-NH 2 . The difference between EDX analysis and SEM-elemental mapping is confirmed by the structure of Fe 3 O 4 @Co(BDC)-NH 2 .
In another investigation, the particle size and shape, as well as the morphology of Fe 3 O 4 @Co(BDC)-NH 2 were examined by scanning electron microscope (SEM) (Fig. 4). As shown in Fig. 4, nano-spherical particles of the nanomagnetic metal-organic frameworks (NMMOFs) are in the nanoscale, as the particles are quite overlapped with different crystallite size as observed in SEM Transmission electron microcopy (TEM) images of Fe 3 O 4 @ Co(BDC)-NH 2 catalyst reveal that the particles shape is spherical and the particle size is up to 50 nm (Fig. 5).   In another investigation, the structural and thermal stability of Fe 3 O 4 @Co(BDC)-NH 2 was also determined using the technique of the thermal gravimetric (TG), derivative thermal gravimetric (DTG), as well as the differential thermal analysis (DTA) ( Figure S4 see in supporting information). First stage weight loss is about 100 °C, associated with the removal of possible solvents (organic and water), which was used in the course of catalyst preparation. Then, twice a step of weight loss has occurred at about 300 °C, which is the onset of the structural degradation of the catalyst.
For the determination of surface structural parameters, the N 2 adsorption/desorption technique was used. The results of N 2 adsorption/desorption were plotted in Fig. 7. The obtained surface area based on BET isotherm is 22.35 m 2 g −1 . The total pore volume of the catalyst is 0.02 cm 3 g −1 . Also, for studying the textural properties of MOF-Co(BDC)-NH 2 the N 2 adsorption-desorption isotherms were used (Fig. 7). The adsorption isotherm is type III and the appearance of hysteresis loop shows the presence of mesopores in the sample. The calculated surface areas based on BET equation and total pore volumes are 86 m 2 g −1 and 0.36 cm 3 g −1 respectively. The pore size distribution of MOF-Co(BDC)-NH 2 based on BJH method is shown ( Figure S5 see in supporting   Table 1. As shown in Table 1 Table 1). The model reaction was also studied by using several solvents such as H 2 O, CH 3 CN, n-hexane, CHCl 3 , MeOH, EtOH, CH 2 Cl 2 , EtOAc (5 mL) and solvent-free condition in the presence of 10 mg of Fe 3 O 4 @Co(BDC)-NH 2 . The results of the reaction did not improve (Table 1, entries [6][7][8][9][10][11][12][13]. Also, the model reaction was also studied in the magnetic stirrer condition at room temperature under the solvent-free reaction ( Table 1, entry 14).
In the proposed mechanism, the aldehyde is activated by Fe 3 O 4 @Co(BDC)-NH 2 . In the initial step, intermediate (I) is produced by the reaction of pyrimidine (R 2 = H, Me) and activated aldehyde. In the next step,  www.nature.com/scientificreports/ nanomagnetic metal-organic frameworks (NMMOFs) catalyst was separated by an external magnet, washed with DMF and dried. The results indicated that the catalyst could be utilized for nine runs without any significant loss of its initial catalytic activity, which can be ascribed to the high stability of the synthesized catalyst (Fig. 8). Then, the reused catalyst was also characterized by FT-IR spectrum ( Figure S6 see supporting information), N 2 adsorption-desorption isotherm (BET) and scanning electron microscope (SEM) images. The obtained spectra are as same as the corresponding spectra of fresh catalyst (Figures S7, S8 see supporting information), Furthermore, to compare the performance of nanomagnetic metal-organic frameworks (NMMOFs) catalyst for the synthesis of desired fused pyridines and 1,4-dihydropyridines with pyrazole and pyrimidine moieties via a cooperative vinylogous anomeric based oxidation, we have used various organic and inorganic acid catalysts for condensation reaction between 4-nitro benzaldehyde (1.0 mmol, 0.151 g), 3-methyl-1-phenyl-1H-pyrazole-5-amine (1.0 mmol, 0.174 g) and pyrimidine-2,4,6(1H,3H,5H)-trione (1.0 mmol, 0.128 g). As Table 3 indicates, Fe 3 O 4 @Co(BDC)-NH 2 is the best of choice for the synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine-5,7(6H)-dione (Table 3).

Conclusion
In summary, a novel core-shell nanomagnetic metal-organic frameworks Fe 3 O 4 @Co(BDC)-NH 2 as a new catalyst was prepared and fully characterized. This catalyst was applied for the synthesis of a range of novel fused pyridines and 1,4-dihydropyridines with pyrazole and pyrimidine moieties with good yields via a cooperative vinylogous anomeric based oxidation mechanism under ultrasonic irradiation. The obtained biological-based compounds are suitable candidates for biological studies. The described catalyst is reusable and easily separated by an external magnet.    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/.