A Green Synthesis of Novel Derivatives of Thiazole-5-One Using Magnetic Supported Copper Nanocatalyst (γ-Fe2O3@HAp@CPTMS@AT@Cu(ӀI))

Abstract A highly efficient one-pot three-component protocol was devised for the synthesis of novel derivatives of ((phenylethlidene)hydrazinyl)thiazol-4(5H)one by the reaction of acetophenone derivatives, ethyl chloroacetate and thiosemicarbazide, in ethanol at room temperature in the presence of copper supported hydroxyapatite-encapsulated-γ-Fe2O3 (γ-Fe2O3@HAp@CPTMS@AT@Cu(ӀI)) as the new magnetically recyclable heterogeneous nanocatalyst. This novel protocol furnished the desired products in excellent yields (88–95%) and short reaction times (20–28 min). The structure and morphology of the synthesized catalyst were characterized by using various techniques such as FT-IR, Fe-SEM, EDX, XRD, TGA-DTA, and VSM. Graphical Abstract


Introduction
Thiazole as an important heterocyclic scaffold is the main constituent of numerous medicinal and biologically important compounds and has attracted many interests.0][11] Besides, the effective use of nanomaterials in catalysis, as rapidly growing field, in synthetic organic chemistry, has gained special importance.8][19][20][21][22][23][24] The synthetic and biological importance of thiazole derivatives have drawn especial attention of synthetic and medicinal chemists to carry out extensive efforts to produce versatile methods and combinatorial library such as, one-pot synthesis via reaction of various a-halocarbonyl with thiocarbamoyl derivatives in ethanol under reflux codition, 25 using isocyanides with leaving group in the b-position and with right degree of unsaturation. 26employing various thioureas and b-keto esters, 27 the reaction of thiosemicarbazone and diethyl acetylenedicarboxylate to provide thiazole derivatives with potential anti-inflammatory properties, 28 a review presenting synthesis of various thiazole derivatives with biological potential, 29 one-pot four-step sequential procedure starting from dimethyl cyanodithioimidocarbonate, 30 the reaction of a-chloroacetaldehyde and thioformamide, 31 deep eutectic solvent as catalyst, 32 and one-pot synthesis using nano-SiO 2.

33
Focusing our research interest on the evolution of innovative catalysts and providing practical methods in organic synthesis, [34][35][36][37][38][39][40] we wish to report a straightforward, efficient, and green protocol for the one-pot synthesis of ((phenylethlidene)hydrazinyl)thiazol-4(5H)one derivatives using a cyclocondensation reaction of acetophenone derivatives, ethyl acetoacetate and semicarbazide in the presence of c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) as a novel magnetically recyclable heterogeneous acidic nanocatalyst in ethanol and at room temperature.

Materials
All chemical used in this research were purchased from Merck and Aldrich.Melting points were investigated on a Bϋchi B-545 apparatus in open capillary tubes.FT-IR spectra were obtained on a a-Bruker spectrometer. 1H NMR spectra were performed on a 500 MHz Varian-INOVA in DMSO-d 6 as solvent and tetramethylsilane (TMS) as internal standard. 13C NMR spectra were obtained on a Varian-INOVA 125 MHz in DMSO-d 6 as solvent.XRD was determined on a KEFA Analytical XPERT-PRO.Scanning electron microscope (SEM) measurements were recorded on a model: VP 1450, company: LEO-Germany.Elemental analysis (EDX) was done 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.Thermogravimetric analysis (TGA) was done on an SDT Q600 V20.9 Build 20 thermal analyzer with a heating rate of 10 C min À1 over a temperature range of 25-700 C under flowing Ar.Thin layer chromatography (TLC) was carried out with ethyl acetate: n-hexane 1:3 on TLC Silica gel 60 F 254 .

General procedure for the synthesis of (E)-2-(2-(aryl)hydrazineyl)thiazol-4(5H)-one
A mixture of semicarbazide (1 mmol), diverse derivatives of acetophenone (1 mmol), ethyl chloroacetate (1 mmol), and 0.06 g c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) were stirred in ethanol (3 mL) at room temperature for the required reaction time (Table 4) and the progress of the reaction was monitored by TLC (ethyl acetate: n-hexane 1:3).After completion of the reaction, c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) was removed by an external magnet (1.4 T) and washed with hot DW and ethanol several times, dried and reused in the next run under the same reaction conditions.The reaction mixture after removal of the catalyst was concentrated under vacuum and the residue was recrystallized from ethanol to produce thiazole-5-one products (4a-j).

Results and discussion
According to the continuation of our research in synthesis of momentous heterocycles, we decided to develop an efficient method for the synthesis of novel derivatives of thiazole-5-one in the presence of newly synthesized magnetic nanocatalyst (c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI)).Initially, c-Fe 2 O 3 @HAp@CPTMS@AT was synthesized according to the literature report [34][35][36][37][38] and incorporated with copper chloride to provide (c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI)) magnetic nanoparticles (MNPs) (Scheme 1).The structure of the catalyst was established by using FT-IR, Fe-SEM, EDX, XRD, TGA-DTA, and VSM techniques.

FT-IR analysis
From FT-IR spectrum of c-Fe 2 O 3 @HAp, the observed peaks at 559 and 597 cm À1 are corresponded to the Fe-O stretching vibration of c-Fe 2 O 3 that are overlapping with O-P-O Scheme 1. Synthesis of c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI).
bending vibration of phosphate groups in HAp, the peak at 1025 cm À1 is assigned to P-O stretching vibration which verifies the formation of c-Fe 2 O 3 @HAp nanoparticles.Also, for the c-Fe 2 O 3 @HAp@CPTMS, peaks at 2928 and 1455 cm À1 can be assigned to C-H stretching and bending vibration of the methylene group, respectively and the observed peak at 1090 cm À1 is related to Si-O stretching vibration that proves the successful stabilization of chloropropyl groups on c-Fe 2 O 3 @HAp.The results obtained from FT-IR spectrum of c-Fe 2 O 3 @ HAp@CPTMS@AT@Cu(ӀI) nanoparticles well showed the stretching vibration of Fe-O at 560 and 598 cm À1 .The stretching vibrations of P-O bands appeared at 1027 cm À1 .The peaks observed in 1640 and 3443 cm À1 are related to the stretching vibrations of C¼N and NH group of the triazole ring, respectively (Figure 2).
3.5.TGA-DTA image of c-Fe 2 O 3 @HAp@CPTMS@at@Cu(ӀI) The thermal stability of c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) was examined by thermogravimetric analysis (TGA) under an Argon atmosphere (Figure 6).It was performed from 28.5 C to 598 C. Weight losses at temperatures below 100 C could be due to the removal of adsorbed water or organic solvents in the nanoparticles.The weight loss in the temperature range of 300-600 C is basically due to the thermal decomposition of the organic layer grafted to the surface of the MNPs.
Following our continued studies in the benign synthesis of biologically important heterocycles, we have investigated a facile method for the green synthesis of novel derivatives of thiazole-5-one in the presence of an efficient magnetic nanocatalyst c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI).In this study, a novel three-component reaction of various acetophenone derivatives (1), thiosemicarbazide (2) and ethyl chloroacetate (3) was investigated to provide triazole derivatives (Scheme 2).To optimize the reaction conditions, synthesis of (E)-2-(2-(1-phenylethylidene)hydrazineyl)thiazol-4(5H)-one (4a) was chosen as a model compound.The reaction was carried out in a variety of solvents and various temperatures (Table 1).The EDX image of c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI).
Effect of catalyst types on the reaction time and yield of 4a is demonstrated in Table 2 which confirms the preference of using c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) MNPs as a better catalyst.This can be attributed to the nanostructure of the catalyst carrying Cu(II).The amount of the catalyst was also considered in the synthesis of model compound which proved that the use of 1.3 mol% of the catalyst per mmol substrate leads to the best yield of triazolidin-3-thione (4a) (Table 3).
The scope of this novel protocol was verified by preparation various triazole products employing arylaldehydes with electron donating and electron withdrawing groups under optimized reaction conditions which provided the products in excellent yield (88-95%) and short reaction time (20-28 min) (Table 4).
A proposed mechanism of the synthesis of triazole derivatives in the presence of c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) is shown in Scheme 3.
Initially, c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) having Lewis acid site activates acetophenone via coordination to carbonyl group.In continuation, thiosemicarbazide is added to the activated carbonyl group producing arylidene intermediate A which is proceeded by reaction of ethylchloroacetate Table 1.Synthesis of 4a using c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) in diverse solvents and temperatures.Scheme 3. A proposed mechanism for the synthesis of triazole drivatives using c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI) nanocatalyst.

Entry
leading to the intermediate B that was followed by interamolecular cyclization to furnish the target products 4a-j.
Recyclability of the catalyst in the synthesis of model compound 4a was also examined.After the end of the reaction, the catalyst was removed by an external magnet, washed with hot ethanol, dried at 80 C, and reused in the subsequent run.It was shown that after five consecutive cycles the catalytic activity was preserved without any striking loss in its catalytic activities.FT-IR of the catalyst after fifth run was mainly similar to the original FT-IR of the catalyst (Figure 8).

Conclusion
Copper supported hydroxyapatite-encapsulated-c-Fe 2 O 3 (c-Fe 2 O 3 @HAp@CPTMS@AT@Cu(ӀI)) as the new magnetically recyclable nanocatalyst was prepared and used as an eco-friendly, efficient nanocatalyst in the green synthesis of novel derivatives of thiazole via the reaction of various acetophenone derivatives, ethyl chloroacetate and thiosemicarbazide in ethanol at room temperature.The main benefits of this research work can be summarized as adherence to the principles of green chemistry, a naive work-up procedure with no need for chromatographic methods, short reaction times, high yields, facile removal, and recyclability of the catalyst.

Figure 1 .
Figure 1.Some representative thiazole derivatives with biological properties.

Table 3 .
Verification of the amount of catalyst used in the synthesis of 4a.
POLYCYCLIC AROMATIC COMPOUNDS
a Isolated.