Design, synthesis and application of a magnetic H-bond catalyst in the preparation of new nicotinonitriles via cooperative vinylogous anomeric-based oxidation

Herein, we designed and synthesized a new H-bond magnetic catalyst with 2-tosyl-N-(3-(triethoxysilyl)propyl)hydrazine-1-carboxamide as a sensitive H-bond donor/acceptor. We created an organic structure with a urea moiety on the magnetic nanoparticles, which can function as a hydrogen bond catalyst. Hydrogen bond catalysts serve as multi-donor/-acceptor sites. Additionally, we utilized magnetic nanoparticles in the production of the target catalyst, giving it the ability to be recycled and easily separated from the reaction medium with an external magnet. We evaluated the catalytic application of Fe3O4@SiO2@tosyl-carboxamide as a new magnetic H-bond catalyst in the synthesis of new nicotinonitrile compounds through a multicomponent reaction under solvent-free and green conditions with high yields (50–73%). We confirmed the structure of Fe3O4@SiO2@tosyl-carboxamide using various techniques. In addition, the structures of the desired nicotinonitriles were confirmed using melting point, 1H-NMR, 13C-NMR and HR-mass spectrometry analysis. The final step of the reaction mechanism was preceded via cooperative vinylogous anomeric-based oxidation (CVABO).


Introduction
Magnetic nanoparticles (MNPs) have special properties.These particles are usually composed of magnetic materials, such as iron, titanium, cobalt, nickel and their corresponding alloys. 1,2he characteristic feature of magnetic nanoparticles is the ability to change their shape and size owing to their nanometer dimensions.4][5] On account of the remarkable properties of magnetic nanoparticles, they are used in numerous elds.For example, in medicine, these particles are used as imaging and therapeutic agents in the diagnosis and treatment of diseases.7][8][9] Magnetic nanoparticles can be modied for catalytic applications and offer suitable catalytic properties using different organic linkers.][12] One of the characteristics of catalysts used in different elds is proper catalytic performance, such as high selectivity, no side reactions and easy separation from the reaction medium with an external magnet. 13,14ydrogen bond catalysts are substances that facilitate secondary bond formation between hydrogen and lone pairs within molecules. 15,16Hydrogen bonds occur when a hydrogen atom is attracted by a lone pair from an electronegative atom (such as oxygen, nitrogen, or uorine) of another molecule.These bonds can signicantly affect the physical and chemical properties of molecules and play an important role in various biological and chemical processes. 17While hydrogen bonding occurs naturally between certain molecules, catalysts can speed up the formation or strengthening of these bonds.Catalysts work by providing an environment or specic functional groups that promote hydrogen bond formation.They can also stabilize transition states during the reaction and reduce the activation energy required for the process. 18,19][22] Nicotinonitriles are a class of organic compounds that contain a nitrile group (-CN) attached to the pyridine ring of RSC Advances PAPER nicotine. 23Various nicotinonitriles that have medicinal and biological properties have been introduced in recent years.5][26] Also, the compounds that have pyridine nuclei in their structure have shown good medicinal properties.Pyridine derivatives have shown anti-inammatory properties and mediators involved in the inammatory process. 27,28They can inhibit cancer cell proliferation, promote apoptosis (cell death) in tumor cells, or interfere with specic molecular targets involved in cancer development.Some pyridine compounds have cardiovascular effects, including vasodilation or inhibition of platelet aggregation, which may be benecial in conditions such as hypertension or thrombotic disorders. 29,30][33] The anomeric effect (AE) is the main driving force for the aromatization of pyridines.Recently, we have introduced anomeric-based oxidation (ABO) via the sharing of electrons of the heteroatom lone pair (X: N, O) at the tetrahedral carbon to the C-H antibonding orbital (nX s*C-H).Also, the role of AE as a strong driving force in organic synthesis has been comprehensively reviewed by four international research groups, including us. 34,35Due to the importance of this concept in promoting the synthesis of organic compounds with biological properties, the development of cooperative vinylogous anomeric-based oxidation (CVABO) is our main interest.][41][42][43] Expanding the design of heterogeneous catalysts is one of the main goals of this report.The importance of magnetic nanoparticles-based catalysts has prompted us to introduce Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst.This catalyst is based on magnetic Fe nanoparticles to create urea moieties on the magnetic nanoparticles.The presence of urea moieties on the structure of a magnetic catalyst enables it to give hydrogen bonds with donor/acceptor sites on the other molecules.The magnetic property of the presented catalyst helps the user to easily separate it from the reaction medium with an external magnet.The synthesized catalyst was used to prepare nicotinonitriles for studying its catalytic performance based on hydrogen bonding activity.

Preparation of 2-tosyl-N-(3-(triethoxysilyl)propyl)hydrazine-1carboxamide as a new H-bond linker
To prepare the target ligand, 10 mmol (1.9 g) of p-toluenesulfonyl chloride was dissolved in 20 mL of THF, and placed in an ice bath.Then, 40 mmol (1.6 mL) of 80% hydrazine hydrate was gradually added.The reaction was stirred for 30 min in an ice bath.Then, the reaction mixture was warmed up to 25 °C and stirred for 2 h.Aer the completion of the reaction, the reaction mixture was decanted into a mixture of EtOAc and H 2 O (2 : 1).Aer that, the organic phase was separated and dried with sodium sulfate.The EtOAc solvent was then evaporated to give p-toluenesulfonyl hydrazide. 44In the next step, 5 mmol (0.93 g) of p-toluenesulfonyl hydrazide and 6 mmol (1.48 g) of triethoxy(3-isocyanatopropyl)silane were added in 10 mL of CH 2 Cl 2 .The mixture was vigorously stirred for 24 h at 40 °C until the reaction was completed.Aer this time, the solvent was evaporated and the obtained solid was washed with CH 2 Cl 2 .Finally, a white powder as a desired linker was obtained.

Preparation of Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst
For the synthesis of the nal catalyst, Fe 3 O 4 @SiO 2 was synthesized according to the previous reports. 45Next, 1 g of  Fe 3 O 4 @SiO 2 was dispersed in 120 mL of toluene using ultrasonic radiation.Then, 2 mmol (0.87 g) of the combined linker was added to the mixture.Then, the obtained mixture was reuxed for 48 h.The resulting catalyst was washed several times with hot toluene.Chloroform was added to the precipitate to remove any unreacted linker.Finally, the obtained catalyst was separated using an external magnet and dried at 100 °C for 24 h.

The general method for the preparation of nicotinonitrile derivatives
First, starting material 3-(4-chlorophenyl)-3-oxopropanenitrile and 1-(dibenzo[b,d]furan-2-yl)ethan-1-one were synthesized according to the previous report. 46For this synthesis, dibenzo [b,d]furan (5 mmol, 0.8 g), acetyl chloride (10 mmol, 0.78 g, 0.91 mL), AlCl 3 (5 mmol, 0.65 g) and CH 2 Cl 2 (30 mL) were added into the 50 mL bottom ask and stirred for 60 min at 25 °C.Aer the completion of the reaction, the reaction mixture was decanted to the mixture of EtOAc and H 2 O (1 : 1) solvents. 47Then, for the synthesis of nicotinonitrile derivatives, a mixture of 1-(dibenzo [b,d]furan-2-yl)ethanone (1 mmol, 0.21 g), 3-(4-chlorophenyl)-3oxopropanenitrile (1 mmol, 0.179 g), ammonium acetate (1.5 mmol, 0.115 g), aromatic aldehyde (1 mmol) and 10 mg of Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst were stirred under solvent-free conditions at 100 °C.The progress of the reaction was monitored using TLC technique (n-hexane and ethyl acetate).When the reaction was completed, hot acetone (15 mL) was poured into the reaction mixture.The catalyst was separated from the reaction mixture with an external magnet.Then, the acetone solvent was evaporated.The remaining solid was washed several times with hot ethanol to obtain the pure product.The structures of the new nicotinonitriles were evaluated and conrmed using melting point, 1 H-NMR, 13 C-NMR and HR-Mass techniques (spectral specications are available in ESI †).

Catalyst preparation strategy
The rational design of catalysts on the basis of hydrogen bonding has received much attention due to their ability to selectively carry out organic reactions. 15,18In this study, a magnetic catalyst based on its hydrogen bonding activity has been designed and synthesized.First, magnetic iron nanoparticles (Fe 3 O 4 ) were synthesized.The primary catalyst bed was designed and synthesized (Fe 3 O 4 @SiO 2 ) by covering SiO 2 on the Fe 3 O 4 .On the other hand, by using p-toluenesulfonyl chloride, hydrazine and triethoxy(3-isocyanatopropyl)silane, a ligand with a urea moiety was synthesized.The abovementioned ligand was reacted with the magnetic nanoparticles to produce Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst under reuxing toluene (Fig. 3).The catalyst designed in this research works based on the hydrogen bonding interaction.The presence of the urea moieties in the catalyst structure creates the connecting part of the H-bond catalysis.The NH groups in urea moieties can activate various functional groups in the structure of raw materials because the presence of carbonyl adjacent to the NH group is susceptible to donor/ acceptor H-bond catalysis.This capability of urea groups has been used to create the target catalyst.The structure of the desired catalyst was approved using various techniques, such as FT-IR, XRD, SEM, EDS, elemental mapping, VSM, TGA and DTG.
The presence of pyridine and nicotinonitrile derivatives in biological derivatives is very important and they show good medicinal properties. 25In line with the development of these materials, aer the design and synthesis of the target catalyst, its catalytic efficiency was evaluated in the synthesis of a wide range of new nicotinonitriles.Fe 3 O 4 @SiO 2 @tosyl-carboxamide showed that it can catalyze the synthesis of target compounds with high efficiency and a relatively suitable reaction time (Fig. 4).The structure of new nicotinonitriles was conrmed using melting point, 1 H-NMR, 13 C-NMR and HR-Mass techniques (spectral specications are available in ESI †).
The structure of new nicotinonitriles was conrmed using melting point, 1 H-NMR, 13 C-NMR and HR-Mass techniques (spectral specications are available in ESI †).The mechanism of the reaction was also investigated.For this purpose, it was observed that the aromatization of the pyridine ring is done through a cooperative vinylogous anomeric based oxidation (CVABO). 36T-IR technique was used to check the functional groups of different stages of catalyst synthesis (Fig. 5).In the FT-IR spectrum of Fe 3 O 4 magnetite nanoparticles, two sharp peaks       of the synthesized linker is also shown in this gure.A comparison of the FT-IR patterns for the synthesized catalyst, Fe 3 O 4 @SiO 2 magnetic substrate, as well as a linker, is shown in Fig. 5.All of the peaks found in different stages of the catalyst synthesis, as well as the corresponding linker, appear in the FT-IR pattern of the nal catalyst, demonstrating the correct synthesis and structure of the catalyst.
The proof of the pattern of crystal plates of Fe 3 O 4 , Fe 3 O 4 @-SiO 2 and Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic Hbond catalyst is shown in Fig. 6 in a comparative way.
The crystal pattern of Fe 3 O 4 agrees well with previous reports. 39Accordingly, the peaks of the areas in 2q = 18.23°, 30.35°, 35.43°, 43.72°, 53.69°, 57.36°, 62.91°and 74.58°correspond to the Fe 3 O 4 diffraction lines (111), ( 220), ( 311), ( 400), ( 422), ( 511), ( 440) and (533), respectively.The wide peak of the 2q = 20-30°, range is related to SiO 2 , which is well placed on Fe 3 O 4 .In the crystal model of the nal catalyst, the peaks corresponding to Fe 3 O 4 and SiO 2 are visible, and the new peaks are probably related to the added linker, which indicates the correct synthesis of the catalyst.Also, to conrm the formation of the synthesized catalyst, the obtained VSM analysis results of all three stages were checked (Fig. 7).
The obtained results of this analysis for the Fe 3 O 4 magnetic nanoparticles showed a high magnetic property with a saturation magnetization of 68 emu g −1 .By placing a SiO 2 coating on Fe 3 O 4 , as expected, a decrease in saturation magnetism was observed (48 emu g −1 ).The VSM analysis of the catalyst showed a lower magnetic property than the initial substrate (22 emu g −1 ), which is a conrmation of the linker immobilization on the surface of the magnetic substrate.
TGA & DTA techniques also were used to prove the thermal stability of the nal synthesized catalyst.According to the obtained results, this catalyst can be used up to a temperature of 230 °C without its structure collapsing (Fig. 8).
SEM analysis was performed to detect the surface morphology of the synthesized catalyst.The SEM micrographs of Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a catalyst showed that the particles were not aggregated, and the cauliower morphology was established for this structure (Fig. 9a and b).The TEM images were recorded with further focusing, and it clearly shows that they are made from nanoparticles and possess a core-shell structure.The TEM results conrmed the obtained data from the SEM images (Fig. 9c and d).

Catalytic performance
To expand the range of nicotinonitrile derivatives, the reaction conditions were optimized.In the optimization conditions, the  The model reaction was investigated in different conditions, such as temperature, amount of catalyst and use/non-use of solvent.Table 1 shows the results of this review.Initially, the model reaction was evaluated at different temperatures under solvent-free conditions with 10 mg of catalyst (entries 1-6).The results showed that the optimal temperature for the highest product yield and the shortest reaction time is 100 °C.Then, the model reaction was tested at this optimal temperature with different amounts of catalyst (entries 7-9).Based on these obtained results, it was found that a suitable result is obtained from only using 10 mg of catalyst.Next, the model reaction with different solvents was evaluated, and the obtained results showed that there is no improvement in the yield and reaction time of the products (entries 10-19).Therefore, the optimum conditions for the synthesis of the target derivative were obtained in solvent-free conditions, at 100 °C, and in the presence of 10 mg of catalyst (entry 4).
The expansion of synthesized compounds is another goal of this report.For this purpose, aer determining the optimal reaction conditions, different aromatic aldehydes with donor and electron acceptor substitutions were used in ideal conditions to prepare a wide range of nicotinonitriles.The results are shown in Table 2.According to the obtained results, products with high efficiency and short reaction time have been obtained, which indicates the proper performance of Fe 3 O 4 @-SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst.
In another study to prove the results obtained from this report, the model reaction was evaluated using other reported organic and inorganic catalysts, as well as the precursors of the initial stages of the presented catalyst.The results are shown in Table 3.According to the obtained results, Fe 3 O 4 @SiO 2 @tosylcarboxamide as a new magnetic H-bond catalyst provides better efficiency and reaction time than other used catalysts.

Catalyst recovery
Catalyst recovery capability has several advantages, including environmental and economic benets that add value to a designed task-specic catalyst.In this report, the recyclability of the catalyst under optimal conditions was investigated.The reaction mixture was dissolved in hot acetone aer each step, and the catalyst was separated using an external magnet.Aer drying, the catalyst was prepared for the next reaction run.Our ndings show that the catalyst can be recycled up to four times without a signicant decrease in its catalytic activity (Fig. 11).FT-IR spectroscopy was used to prove the stability of the recovered catalyst.Fig. 12 shows the spectrum of the recovered catalyst, as well as the fresh catalyst.According to this analysis, the patterns of both spectra are almost similar, which shows the stability of the desired catalyst aer being reused.

Hot filtration test
To verify the catalytic activity of Fe 3 O 4 @SiO 2 @tosylcarboxamide in producing nicotinonitrile derivatives, a hot ltration test was conducted using the model substrate under optimal reaction conditions.Aer 15 minutes of the reaction, it was stopped and the yield was determined to be 20%.In  The catalyst was then separated from the system using an external magnet.Next, the solvent was evaporated and the reaction mixture was further stirred for another 1 h at the same optimum conditions.There was no noticeable improvement in the reaction yield.An ICP-OES test was also carried out for further investigation, revealing that 0.0055 × 10 −6 mol per g Fe remained in the product.Therefore, it appeared that the reaction progressed with little efficiency aer the catalyst was removed.

Conclusion
In summary, we designed a magnetic catalyst modied with 2tosyl-N-(3-(triethoxysilyl)propyl)hydrazine-1-carboxamide as an organic linker.By using and designing this method, urea groups were created on the nanoparticle structure, which turned it into a targeted catalyst with hydrogen bonding ability.
The presented catalyst has recycle and reuse ability.It can be easily separated from the reaction medium with an external magnet.The structure of the target catalyst and synthesized new nicotinonitriles were conrmed using various techniques.The major advantages of the presented methodology are the recycling and reusing of the reported catalyst, high yield of products, and solvent-free and green conditions.Fig. 12 FT-IR spectra of the fresh and reused catalysts.

Fig. 1
Fig. 1 Structure of medicinal compounds containing nicotinonitrile and pyridine groups.

Fig. 4
Fig.4Catalytic application strategy for the preparation of nicotinonitrile derivatives using Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst.

Fig. 5
Fig. 5 FT-IR spectra of different stages of the synthesis of the catalyst.

Fig. 9
Fig. 9 Scanning electron microscopy (SEM) (a and b) and transmission electron microscopy (TEM) (c and d) images of Fe 3 O 4 @SiO 2 @tosylcarboxamide as a new magnetic H-bond catalyst.

Fig. 10
Fig.10Proposed mechanism for the synthesis of nicotinonitrile derivatives using Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst.

Fig. 11
Fig. 11 Recyclability of the catalyst in the synthesis of nicotinonitrile derivatives.

Table 1
Optimizing the conditions for the synthesis of nicotinonitrile derivatives a Aer releasing one molecule of H 2 O, intermediate (I) is produced.On the other hand, ammonium obtained from ammonium acetate reacts with 1-(dibenzo[b,d]furan-2-yl)ethenone and intermediate (I) is produced, which acts as a Michael acceptor, and intermediate (II) is created.Intermediate (II) undergoes tautomerization and intramolecular cyclization is converted to intermediate (III).Intermediate (III) is converted to intermediate (IV) by removing another H 2 O molecule.Finally, 1,4dihydropyridines (IV) are converted to the corresponding pyridine derivatives via the CVABO mechanism, liberating a molecule of hydrogen (H 2 ) and/or hydrogen peroxide (H 2 O 2 ) 36,

Table 2
Catalytic synthesis of nicotinonitrile derivatives in the presence of Fe 3 O 4 @SiO 2 @tosyl-carboxamide as a new magnetic H-bond catalyst