Pyrrolidinium Acetate (PyrrIL) as a Green and Recyclable Catalyst: Synthesis of 2-Phenyl Benzimidazoles and 2-Phenyl Benzothi-azoles under Solvent-Free Conditions at Room Temperature

Benzimidazoles and benzothiazoles are a class of pharmaco-logically potential compounds, which exhibited antimicrobial, anticancer, and anti-inflammatory activities. These can be obtained by simple condensation of o -phenylenediamine or o -aminothiophenol with aromatic aldehydes. The synthetic protocol can be accomplished/improved by varying reaction parameters such as temperature, solvents, and catalysts. To develop such condensation reactions in a sustainable way, nontoxic solvents and eco-friendly catalysts are presently used. In this study, we proposed a novel and interesting strategy for obtaining di-versely substituted 2-phenyl benzimidazole and 2-phenyl benzothiazole derivatives via a one-pot protocol, employing pyrrolidinium ionic liquid as a green and environmentally benign catalyst under solvent-free conditions at room temperature in an open atmosphere. The resulting products were obtained in good to excellent yields within a short reaction time (3–20 min). A plausible mechanism was also discussed.

The synthesis of heterocyclic compounds utilizing green chemistry principles is significantly important in modern organic chemistry. For example, reactions involving ecofriendly, recyclable catalysts, green solvents, and nontoxic reactants are essential in the production of pharmaceutically important compounds.
Ionic liquids (ILs) have shown potential properties as greener solvents or catalysts in the replacement of organic solvents and catalysts over the last decades. These are stable at high temperatures, low-volatile, environmentally benign, and recyclable, even though more expensive than other organic solvents. 1 In organic synthesis, it is crucial and desirable to employ affordable cations and anions. 2 Numerous studies have demonstrated that ionic liquids serve as solvents and catalysts in organic synthesis. These can be utilized as solvents in the presence of other catalysts or as catalysts in the presence of other solvents. [3][4][5] Anouti and co-workers synthesized 6 and characterized the ionic liquids utilizing pyrrolidine as the cation source and formate, acetate, and trifluoroacetate as the anions. The pyrrolidinium-based ionic liquids are protic ionic liquids (PILs), which are often inexpensive and less hazardous than other ionic liquids. These ionic liquids are superionic with a broad spectrum of potential uses, in acid-catalyzed reactions, fuel cell devices, dye-sensitized solar cells, and thermal transfer fluids. [7][8][9][10]

Figure 1 Bioactive motifs containing benzimidazole and benzothiazole skeletons
Benzimidazoles and benzothiazoles, which contain a five-membered ring fused to a six-membered ring, belong to fused heterocycles and are responsible for a broad spectrum of properties in domains like agrochemicals, pharmaceuticals, and natural products. [11][12][13] These fused heterocyclic scaffolds have been associated with numerous biologically active molecules ( Figure 1). 14,15 Benzothiazole derivatives are present in a variety of terrestrial and marine natural products with a wide range of applications. 16,17
The above-mentioned reports contain drawbacks, such as the use of hazardous reagents, solvents, expensive catalysts, prolonged reaction times, high temperatures, and harsh reaction conditions, as well as the formation of unwanted products. The methodologies employing green catalysts, such as nonmetal salts, heterogeneous recyclable catalysts, or ionic liquids, 44-51 and green solvents, or solvent-free or microwave or ultrasonic conditions, 52-54 are desirable to promote sustainable eco-friendly research. [55][56][57] In this regard, ionic liquids have shown promising results in a variety of synthetic processes because of their great selectivity and catalytic efficiency. [58][59][60][61] Due to the significance of these classes of compounds, it is important to develop more sustainable methods. In the present study, various experiments were carried out to evaluate different reaction conditions to obtain 2-phenyl benzimidazole and 2-phenyl benzothiazole compounds in the absence of metal salts as catalysts, as well as under solvent-free conditions or in the presence of nontoxic solvents. The investigations described in this study are aimed to utilize ionic liquid as a catalytic alternative, which made it easier to perform several experiments and provided the desired products in excellent yields within a short reaction time (Scheme 1). Initially, various ionic liquids are prepared by combining different carboxylic acids, such as formic acid, acetic acid, or trifluoracetic acid, with pyrrolidine by following the literature methods ( Figure 2). 2,6

Figure 2 Pyrrolidinium ionic liquids
The ionic liquids were used as catalysts to obtain benzimidazole and benzothiazole derivatives through a simple condensation reaction involving o-phenylenediamine (1) or o-amino thiophenol (2) with aromatic aldehydes 3a-q containing variable substituents on the ring affording a series of desired products with excellent yields (4a-q). These reactions were conducted under solvent-free conditions and at ambient temperature, providing diversely functionalized compounds as shown in Scheme 1.
To establish the scope of this methodology, a number of experiments were conducted employing different solvents, catalysts, temperatures, and reaction times ( Table 1). The reaction between o-phenylenediamine (1) and salicylaldehyde (3o) was conducted as a model reaction in the absence of a catalyst and a solvent, resulting in a trace amount of the product ( Table 1, entry 1). Several solvents such as EtOH, MeOH, DCM, CHCl 3 , H 2 O, acetic acid, and sodium acetate were employed to examine the suitability, and the products were obtained in the range of 28-53% (Table 1, entries 4-8, 11, and 12). Further, the reaction was performed under reflux conditions also resulting in the product in 56% (Table 1, entry 9).
To improve the yields, the model reaction was carried out in the presence of the catalyst pyrrolidinium acetate, in the absence of solvent, and the yield was encouraging (Table 1, entry 10). The optimization experiments revealed that the product was obtained in maximum yield when the reaction was conducted in the presence of the catalyst pyrrolidinium acetate under solvent-free conditions (  Table 2, entry 2). The influence of different catalyst concentrations of pyrrolidinium acetate was assessed at 0.5, 1.0, and 2.0 mL, obtaining the desired product in 76% and 96% yield, respectively (Table 2, entries 2, 4, 5). There was no significant improvement even when that catalyst quantity was doubled from 1.0 to 2.0 mL ( Table 2, entry 5).
Moreover, the catalytic efficiency of pyrrolidinium acetate was assessed in the model reaction employing ophenylenediamine and salicylaldehyde under solvent-free conditions at room temperature ( Figure 3). The ionic liquid was recycled and reused up to four consecutive cycles without significant loss of activity ( Figure 3

Figure 3 Recyclability of pyrrolidinium acetate
All the chemicals were purchased from Sigma Aldrich with purity not less than 99.9%. Analytical thin-layer chromatography (TLC) was carried out by using silica gel 60 F254 pre-coated plates. Visualization was accomplished with UV lamp of I 2 stain. All the products were characterized by their NMR and mass spectra. 1 H NMR and 13 C NMR spectra were recorded on 400 or 200 MHz, in DMSO and CDCl 3 , and the chemical shifts were reported in parts per million (ppm, ) downfield from the tetramethyl silane.

Pyrrolidinium Acetate Catalyst
Pyrrolidine (1.0 mmol, 10 g) is placed in a three-neck round-bottom flask immersed in an ice bath and equipped with a reflux condenser, a dropping funnel to add acetic acid, and a thermometer to monitor the temperature. Under vigorous stirring, acetic acid (2.47 mmol, 20.85 g) is added dropwise to pyrrolidine (60 min). The temperature is maintained less than 25 °C during the addition of the acid by use of the ice bath. Stirring is maintained for 4 h at ambient temperature, and a low-viscous liquid is obtained. This new phase is yellow-pale colored. The residual pyrrolidine or acid is evaporated under reduced pressure and the remaining liquid is further dried at 80 °C under reduced pressure (1-5 mmHg) to obtain pyrrolidinium acetate catalyst (18.05 g; yield 98%). 6 The same procedure was applied to synthesize other ionic liquids, such as a pyrrolidium format [

2-Phenyl Benzimidazoles Mediated by Ionic Liquid
o-Phenylenediamine (1.0 mmol), benzaldehydes (1.0 mmol), and pyrrolidinium acetate (7.62 mmol (1 mL) with respect to the o-phenylenediamine) were taken in a 25 mL round-bottom flask. Then, the reaction mixture was stirred at room temperature for 3-15 min. After completion of the reaction as indicated by TLC, the crude residue was extracted with diethyl ether (3 × 10 mL) and water. The organic layer was washed with brine solution and dried over MgSO 4 . The combined organic layers were evaporated under reduced pressure, and the resulting crude product was purified by column chromatography using ethyl acetate and hexane (1:9) as eluents. Some of them (solids) were recrystallized using appropriate solvents. Further, the residual ionic liquid catalyst was dried under vacuum at 80 °C for 4 h, which could be reused for further cycles without loss of its catalytic activity. The identity and purity of the products were confirmed by comparing with the authentic samples and also confirmed by 1 H NMR, 13 C NMR, and mass spectra. 14,15