An efficient green synthesis of polyfunctional pyrazole-triazole hybrids and bis- triazoles via chromium incorporated fluorapatite encapsulated iron oxide nanocatalyst

Article history: Received December 18, 2020 Received in revised form April 23, 2021 Accepted April 23, 2021 Available online April 26, 2021 In this report, novel chromium incorporated fluorapatite encapsulated iron oxide (γFe2O3@FAp@Cr) nanocatalyst was synthesized and characterized by FT-IR, TEM, SEM, XRD and EDX techniques. The catalyst was used in the synthesis of various derivatives of pyrazoletriazole hybrids via the reaction of thiosemicarbazide or semicarbaside and pyrazolecarbaldehydes at room temperature with excellent yields and short reaction times. The protocol was also used in the synthesis of bis-triazoles in high yield and reasonable reaction time. The nanocatalyst was comfortably separated from the reaction mixture by an external magnet and was reused in six consecutive cycles without any remarkable changes in its catalytic performance. © 2021 Growing Science Ltd. All rights reserved.


Introduction
Nitrogen containing heterocyclic rings are momentous groups in organic chemistry. Derivatives of triazole rings are an essential aromatic five-membered heterocycles presenting important biological activities [1][2][3][4][5][6][7] . Some of these compounds have shown anti-bacterial 8,9 , anti-fungal 10 , antiinflammatory 11,12 , anti-tumor 13,14 , antimalarial 15,16 and anti-cancer 17,18 properties. Numerous derivatives of triazole rings are widespread in natural product and pharmacological compounds. Some representative examples are presented in Fig. 1 [19][20][21][22][23][24][25][26] . Therefore, various methods and catalysts have been introduced for the synthesis of triazole derivatives such as, application of a microwave-assisted click chemistry using copper(I) 19 , samarium doped fluorapatites 27 , [C16MPy]AlCl3Br as ionic liquid 28 and potassium hydroxide 29 . Nevertheless, the most general method for the synthesis of five-membered heterocycles is [3+2] cycloaddition reaction which has been recently discussed in detail 30 . Some of the reported procedures suffer from harsh reaction conditions, complex synthetic pathways and non-recyclability of the catalyst. Consequently, more facile synthetic methods are still required. To achieve this objective, we developed an efficient protocol by using the magnetic chromium incorporated fluoroapatite (γ-Fe2O3@FAp@Cr) as a novel catalyst for the green synthesis of versatile polyfunctional pyrazole-triazole hybrids in short reaction time (10-60 min) and excellent yield (88-95%). Interestingly, the method was also extended to the synthesis of bis-triazoles successfully.

Results and Discussion
Following our continued studies in the benign synthesis of biologically important heterocycles 31-39 , we have developed a convenient method for the efficient synthesis of mono-and bis-triazole in the presence of newly synthesized magnetic nanocatalyst (γ-Fe2O3@FAp@Cr). Initially, the requisite γ-Fe2O3@FAp was prepared according to the literature report 37,38 and reacted with CrCl3.6H2O in water at room temperature to furnish the desired catalyst (Scheme 1). The structure of the catalyst was established by FT-IR, XRD, SEM, EDX and TEM.

FT-IR analysis
In the FT-IR spectra of γ-Fe2O3@FAp@Cr NPs the bending vibrations of P-O-P which are overlapping with the stretching vibration of Fe-O are visible at 589 and 604 cm -1 . The stretching vibrations of P-O bands appeared at 1039 cm -1 . The broad and strong band at 3415 cm -1 belongs to the stretching vibrations of O-H groups and absorbed water (Fig. 2)   Scanning electron microscopy analysis (SEM) The morphology and particle size of the γ-Fe2O3@FAp@Cr catalyst were investigated using SEM technique (Fig. 4). According to the SEM images γ-Fe2O3@FAp@Cr MNPs are formed with almost spherical morphology. The average size of γ-Fe2O3@FAp@Cr nanoparticles is about 15-40 nm according to the measurement software.

TEM analysis
The morphology and size of the γ-Fe2O3@FAp@Cr MNPs were checked by the TEM spectrum as shown in Fig. 6. According to the TEM images analysis, the size of these nanoparticles was estimated 15-25 nm.
In order to study the catalytic capability of the synthesized γ-Fe2O3@FAp@Cr nanoparticles in organic reactions, we decided to investigate its activity in a green synthesis of several pyrazole-triazole hybrids (Scheme 1). Therefore, for optimization of the reaction conditions as a model reaction, thiosmicarbazide or semicarbazide (1) and 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (2) in the presence of γ-Fe2O3@FAp@Cr nanoparticles in a variety of solvents and various temperatures were reacted ( Table 1).
It is evident from the results that using chloroform at room temperature leads to the desired product 5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,2,4-triazolidin-3-thione (3a) in 10 min and 95% yield (Table 1, Entry 4). To demonstrate the efficiency of the nanocatalyst the reaction was performed in the absence of the catalyst and in the presence of various acidic and basic catalysts ( Table 2). This study revealed that the reaction in the presence of γ-Fe2O3@FAp@Cr nanocatalyst produces better result. The amount of the catalyst was also verified which proved that the use of 0.06 gr (4.7 mol%) of the catalyst per mmol substrate provides the best yield of triazolidin-3-thione (3a).   This protocol was applied to the synthesis of a variety of pyrazole-triazole hybrids by using substituted pyrazole carbaldehydes (2) under the optimized reaction conditions and the results are presented in Table 4. This study reveals that both thiosemicarbazide (Enties 1-6) and semicarbazide (Entry 7) provide the desired products (Scheme 1) in high to excellent yields (88-95 %) and lower reaction times (10-15 min). The synthesis of model compound (3a) in ethanol or methanol at room temperature provided 5alkoxy-3-(3-(3-aryl)-1-phenyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole derivatives (4a-e) (Scheme 2) in excellent yields ( Table 5)  Interesting results obtained in the synthesis of pyrazole-triazole hybrids ( Tables 4 & 5) encouraged us to extend the scoop of this protocol to the synthesis of bis-triazole derivatives (7a-c) (Scheme 3). Initially, the reaction of 1,4-dibromobutane with thiosemicarbazide resulted in the synthesis of butane-1,4-diyl-bis(hydrazinecarbimidothioate) which then reacted with various aromatic aldehydes to furnish the novel derivatives of bis-triazoles in excellent yields and reasonable reaction times ( Table 6). Structure of these new bis-triazole derivatives were established by spectroscopic (FT-IR, 1 H NMR, 13

Scheme 3.
Synthesis of novel derivatives of bis-triazoles using γ-Fe2O3@FAp@Cr. A suggested mechanism for the synthesis of triazole derivatives in the presence of chromium incorporated fluorapatite encapsulated iron oxide nanocatalyst (γ-Fe2O3@FAp@Cr) is presented in Scheme 4. Initially, γ-Fe2O3@FAp@Cr NPs activate pyrazolecarbaldehyde via coordination to the carbonyl group of the aldehyde. In continuation, thiosemicarbazide or semicarbazide is added to the activated carbonyl group of aldehyde producing arylidene intermediates A or B which by interamolecular cyclization furnish the target products 3a-g, 4a-e and 7a-c.
The recyclability of the catalyst was investigated in the synthesis of model compound 3a. At the end of each reaction the nanocatalyst was separated by an external magnet, washed with hot ethanol, dried at 80°C and reused in the subsequent run. This study showed that after six consecutive cycles the catalytic activity was preserved without any striking loss in its catalytic activities (Fig.7).

Conclusions
We have introduced γ-Fe2O3@FAp@Cr, as an efficient, novel, inexpensive, eco-friendly and recyclable nanocatalyst, for the synthesis of pyrazole-triazol hybrids and bis-triazoles. The prominent advantages of this method can be described as adherence to the basis of green chemistry, easy work-up procedure without any need for chromatographic separation, short reaction times, excellent yields, facile removal and reuse of the catalyst.

Acknowledgements
Partial financial support of University of Guilan for this research work is sincerely acknowledged.

Materials and Methods
Chemicals for this research were purchased from Merck and Fluka. Melting points were determined on a Bϋchi B-545 apparatus in open capillary tubes. FT-IR spectra were recorded on a α-Bruker spectrometer. 1 H NMR spectra were recorded on a 300 MHz Bruker DRX-300 in DMSO-d6 as solvent and tetramethylsilane (TMS) as internal standard. 13 C NMR spectra were obtained on a 75 MHz Bruker DRX-75 in DMSO-d6 as solvent. Mass spectra were obtained from AB SCIEX 3200 QTRAP. XRD was done on a KEFA Analytical XPERT-PRO. Scanning Electron Microscope (SEM) were investigated on a model: VP 1450, company: LEO-Germany. Elemental analysis (EDX) was obtained on Oxford Instruments EDS Microanalysis X-MAX-80; model: TeScan-Mira III. Transmission electron microscopy (TEM) measurements were recorded on a Zeiss-EM10C-100 KV instrument. Thin layer chromatography (TLC) was done with ethyl acetate: n-hexane 1:1 on TLC Silica gel 60 F₂₅₄.

Synthesis of γ-Fe2O3@FAp@Cr
MNPs γ-Fe2O3@FAp MNPs was prepared according to the reports 37,38 . 125 mg of γ-Fe2O3@FAp was stirred with 2 mmol CrCl3.6H2O in 25 ml water at room temperature for a period of 1 h. The obtained slurry was magnetic decanted, washed with DW frequently, and dried at 100 ℃ to give γ-Fe2O3@FAp@Cr NPs as a brown solid (655 mg).