Synthesis, Characterization of TiO2-Based Nanostructure as Efficient Catalyst for the Synthesis of New Heterocycles Benzothiazole-Linked Pyrrolidin-2-One: Catalytic Performances Are Particle’s Size Dependent

Abstract Nano and micro-rutile TiO2 structures were prepared via sol–gel and hydrothermal approaches, respectively. The as-prepared structures were subjected to various characterizations; morphological by Scanning electron microscopy, structural using both X-ray diffraction and Raman spectroscopy and elemental analysis by X-ray photoelectron spectroscopy. The catalytic ability of the two synthesized TiO2 structures were evaluated against the synthesis of new heterocyclic compounds pyrrolidinone linked to benzothiazole moiety. These scaffolds have been prepared from substituted amines and available 2-aminothiophenol using the as-prepared TiO2 as a heterogeneous catalyst, under ultrasonic irradiation. Our results indicate that the hydrothermal-prepared TiO2 provide lower catalytic activity with respect to the sol-gel prepared one. Graphical Abstract


Introduction
Properties and applications of TiO 2 powder is generally associated with its crystal phase, particle size, morphology, and surface properties. As such, the synthesis of TiO 2 nanostructures with controllable shapes and dimensions has aroused a great interest during the last few years and various one, two, or three-dimensional structures have been reported. [1][2][3][4][5][6] Over the last five decades, the use of TiO 2 as catalyst has showed a significant improvement because of the highest catalytic performances. [7][8][9][10][11] In this way, TiO 2 have been applied as nanocatalyst for organic reactions due to its high activity, non-toxicity, availability, stability, easy reusability, high power of oxidizing, and Lewis acidity. 12,13 Moreover, TiO 2 nanocatalyst has been showed a high performance in the Friedel-Crafts reaction, 14 polyhydroquinoline synthesis and Hantzsch ester compounds, 15 a-acetamidoketone synthesis, 16 and bis-(indolyl)methane. 17 Also it has been showed a good efficiency as catalyst for the preparation of xanthene scaffolds, 18 indoles alkylation 19 as well as to synthesize quinoxalines derivatives, 20 quinazolinone, 21 imines, 22 imidazoles 23 and as catalyst for Knoevenagel-Michael-cyclocondensation. 24 On the other hand, substitued 2-pyrrolidinones have gained particular attention due to their various applications in medicinal chemistry. 25 These molecules have shown multiple pharmacological activities such as antimicrobial, 26 antibacterial, 27 Analgesic, 28 Anti-inflammatory, 29 anticonsulvant, 30 anticancer, 31 and also as inhibitors of HIV-1. 32 Therefore, a various synthetic pathways have been reported to prepare pyrrolidinones scaffolds. [33][34][35][36][37][38][39][40][41] Similarly, benzothiazole heterocyles have, too, attracted more interest in the scientific community due to their pharmacological uses. 42 In fact, they have exhibited pronounced anti-cancer, 43 anti-bacterial, 44 anti-tuberculosis, 45 anti-viral, 46 anti-diabetic, 47 anti-tumor, 48 anti-inflammatory, 49 antimicrobial, 50 neuroprotective 51 effects and, also, used as inhibitors for several enzymes. 52 However, many synthetic routes have been reported to prepare benzothiazole scaffolds using nanocatalysts. 53,54 Within the continuity of our reseach program aiming to synthesize new heterocyclic scaffolds by developing new strategies, 55-63 this paper desscribes the synthesis of new 2-pyrrolidinones linked to benzothiazole moity using two different TiO 2 nanostructures as nanocatalysts under ultrasonic irradiation. Principally, comparison of the catalytic performances between two TiO 2 nanostructures was investigated (Scheme 1).

Reagents and chemicals
Tetrabutyl titanate (TBOT, (C 4 H 9 O) 4 Ti, 98%) was the precursor for both sol-gel and hydrothermal preparation of TiO 2 samples. Ethanol and hydrochloric acid (HCl, 38%) were used as additives. The melting points ( C) of the prepared derivatives were recorded in open capillaries using a melting point apparatus (Sanyo Gallenkamp, South borough, UK). Precoated silica gel TLC plates (silica gel 0.25 mm, 60G F2540) purchased from Merck, Germany were employed for TLC experiment whereas, the mobile phase system used for developing purposes consisted of a mixture of (n-hexane: EtOAc (80: 20 v/v)). Elucidation of total proton and carbon numbering and environment was made by recording 1 H-NMR and 13 C-NMR spectra using NMR instrument BRUCKER-PLUS (400 MHz). Microwave model Biotage Initiator Microwave Reactor and Ultrasonic Procesor model UP200Ht (with a frequency 20kHz) were used for completing the experiments performed in the current work.

Rutile TiO 2 nanostructures preparation
Rutile TiO 2 nanopowder (nano-TiO 2 ) was prepared using a standard sol-gel strategy. First, 23 mL of TBOT was added to 23 mL of ethanol and the resulting solution (sol. 1) was vigorously agitated for 30 min. Next, 23 mL of ethanol was mixed with 18 g of 4.4 M HCl solution and kept under stirring for 15 min (sol. 2). Afterwards, Sol. 2 was, dropwise, added to the former solution (sol. 1) under sonication and at room temperature. The obtained mixture was held for hydrolysis in an incubator at 40 C for 4 days. The collected dried gel was, finally, milled and calcined at 600 C for 2 h holding the heating rate at 20 C/min. Hierarchical TiO 2 microspheres (H-TiO 2 ) were prepared following a typical hydrothermal process. Explicitly, 25 mL of 7.5 M HCl was added to 25 mL of TBOT under stirring. The mixture was stirred for 20 min and then transferred into a 50 mL Teflon-lined stainless steel autoclave and kept at 160 C for 24 h. After cooling at room temperature, the resulting powder was filtered, washed with deionized water, then, dried at 70 C to obtain the final product.

General procedures of synthesis
General procedure of prepartion of derivatives type 3 An equimolar mixtue of dimethylitaconate 1 (15 mmol) and amine 2 (15 mmol) was irradiated in microwave in presence of water as solvent. After 20 minutes of irradiation, the mixture was poured in ice. After filtration, the collected solid was washed with ethanol to achieve the pure intermediate type 3.
General procedure of prepartion of derivatives type 5 A mixture of substitued methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate (1 mmol) 2-aminothiophenol (1 mmol) in TiO 2 nanostructure (20 mg) in ethanol (20 mL) was sonicated for the suitable time. The mixture was poured in a beaker containing water (50 mL), stirred for 10 minutes. The crude solid was filtered. The pure final products were obtained via purification through a column chromatography using n-hexane/EtOAc (80: 20 v/v) as eluent.

Morphological analysis
Morphological features (shape and dimension) of TiO 2 are well believed to be closely related to the synthetic route chosen and also have a critical impact on its physico-chemical properties which determine its applications. 64,65 Generally, sol-gel synthesis methods yield nanosized TiO 2 particles, 66,67 while hydrothermal based synthesis route yields TiO 2 microstructures. 68,69 The SEM images of the nano-TiO 2 and H-TiO 2 samples are displayed in Figure 1. The nano-TiO 2 sample shows a porous structure of almost capsule-like shaped nanoparticles with a diameter and a length about 20 nm and 80 nm, respectively.
On the other hand, the morphological overview of H-TiO 2 sample displays a well-defined microspheres with diameters ranging from 3 to 5 mm (Figure 1a). These microspheres are formed by a large number of very dense outward-radiating nanorod-like structures with a typical average diameter about 70 nm.

Structural analysis
The crystal structures of as-prepared samples were, first, examined by XRD and their patterns are presented in Figure 2 70 These observed diffractions are consistent with the reported XRD pattern for the rutile phase of TiO 2 . Despite this, the nano-TiO 2 displays a clear higher peaks intensities than H-TiO 2 reflecting its higher crystallinity probably associated with the effect of the calcination step processed only for the preparation of the nano-TiO 2 . In addition to the XRD study, Raman spectroscopy analysis was performed to gather more information about the structural phase of nano-TiO 2 and H-TiO 2 samples. The corresponding recorded spectra are displayed in Figure 3. Three main Raman active bands located at 232, 447, and 609 cm À1 corresponding to the multiphoton process, Eg, and A1g modes of rutile TiO 2, 71 respectively, were clearly observed for both samples. Indeed, the two samples showed a similar Raman peak pattern to that reported for rutile TiO 2 which is consistent with the above-mentioned XRD observations.

XPS elemental analysis
Elemental analysis was conducted on both nano-TiO 2 and H-TiO 2 samples using XPS technique. Typical surveys and high-resolution spectra are displayed in Figure 4a. The calibration of the binding energy is done by fixing the C 1 s line to 286 eV. The surveys spectra of the nano-TiO 2 and H-TiO 2 contains the Ti2p and O1s characteristic peaks of TiO 2 (Figure 4) confirming the effectiveness of synthetic methods.   (Figure.4c), and correspond, also, to Ti 2p1/2 and Ti 2p3/2 spin-orbit splitting. These two peaks are separated by 5.64 eV, which matches well with the reported literature values. 72,73 The high resolution O1s signal for nano-TiO 2 shown in Figure, is characterized by a central peak at 530.88 eV recognized to be assigned to the bulk oxide (O 2-), followed by a second peak located at 532.28 eV the Ti-O-C bonding (Figure 4d). Likewise, the O1s spectrum of H-TiO 2 can be resolved into three bands (Figure 4e): a central band at 530.02 eV is attributed to the lattice oxygen (Ti-O-Ti), a band at 531.08 eV allocated to the hydroxyl (OH) and a band at 532.08 eV assigned to the Ti-O-C bonding, likely due to adsorbed CO 2. 74 Remarkably, as revealed by XPS analysis the H-TiO 2 sample appeared to be more hydroxylated (35% TiOH) than the nano-TiO 2 (TiOH free) because it was hydrothermally prepared and not calcined.

Catalytic performance
Condition optimization of construction of heterocycle type 5 As a first step to prepare derivatives 5, intermediates substituted methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate 3 were synthesized from different substituted benzylamines in the presence of 1 and water as the solvent under microwave irradiation (Scheme 2). Initially, reaction conditions were optimized using 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester 3a and 2-aminothiophenol 4 as the model. Table 1 summarizes the effect of various conditions. Scheme 2. Synthetic route for substituted methyl 1-benzyl-5-oxopyrrolidine-3-carboxylate. In the presence of H-TiO 2 , low reaction yields were obtained by using water, DMF, acetone, chloroform (entries 1-4, Table 1). When ethanol was used as the reaction medium in presence of H-TiO 2 and Nano-TiO 2 under classical reflux, compound 5a was obtained in a yield of 56% or 90%, respectively (entries 5 and 6, respectively, Table 1). Besides, the use of water as solvent afforded the final products in relatively lower yields (entries 7 and 8, respectively, Table 1). However, when the reaction was lunched under ultrasonic irradiation, a better product yield of 56% or 90%, respectively, was obtained (entries 9 and 10, respectively, Table 1). On the other hand, in the absence of the catalyst, the heterocycle was obtained in moderate yields (entries 11, Table 1). Notably, the use of a mixture of nano-TiO 2 with ethanol compared to H-TiO 2 afforded 5a with yields of up to 90% (entries 8, Table 1) in only 30 min. Overall, compared to other catalysts, our strategy afforded the final product with outstanding yields in an extremely short time of 30 min (entries 12 and 13, Table 1).
Derivatives 5a-j were produced in excellent yields using TiO 2 nanoparticles in just 20 minutes, however the use of the hierarchical TiO 2 decrease the reaction productivity and only lower yields were achieved ( Table 2). All reactions were carried out by reacting 2-aminothiophenol 4 with different substituted intermediates type 3. Remarkably, substitution of the intermediate 3 shows no  influence on the final heterocycle construction in both nanostructures and reactions produce the final compounds with high yields in very short time (20 min).
In addition, the recyclability of the nano-TiO 2 catalyst was studied. The recycled nano-TiO 2 catalyst was recovered by filtration from each reaction and reused for the next reaction. The final derivative yield was slightly decreased (Table 3).
A plausible mechanism for the reaction between 3 and 4 using the TiO 2 catalyst was proposed in Figure 5.

Conclusion
In summary, a nanostructure-based strategy has been developed to prepare a novel heterocycle by linking two important moieties via an efficient strategy. The simple reaction conditions, availability of starting chemicals and the clean route mediated two different TiO 2 nanostructures present the main advantages of the developed process. The comparison of the catalytic performance of the two nanostructures showed that TiO 2 nanoparticles are more efficient than the hierarchical nanospheres.