Eco-Friendly and Facile Synthesis of Substituted Imidazoles via Nano Zirconia Catalyzed One-Pot Multicomponent Reaction of Isatin Derivatives with Ammonium Acetate and Substituted Aromatic Aldehydes under Solvent Free Conditions

An eco-friendly and highly efficient approach for the synthesis of substituted imidazoles via nano zirconia catalyzed multicomponent reaction of isatin derivatives with ammonium acetate and aromatic aldehydes under solvent-free conditions has been developed. This approach can be mostly applied to medicinal chemistry due of the simple and readily available starting materials, effortless methodology, and biologically active nature of imidazoles. An additional gain of the suggested technique is the reusability of the nano ZrO 2 catalyst.


Introduction
Imidazole is a "1, 3-diazole" and is classified as an alkaloid. Imidazole (1) refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents. This ring system is present in important biological building blocks, such as histidine (2), and the related hormone histamine (3). Imidazole can serve as a base and as a weak acid. Many drugs contain an imidazole ring, such as antifungal drugs and Nitroimidazole (4) [1][2][3][4][5].
Imidazole derivatives are mostly used as organic resources [6,7] and it also plays important roles in various types of biological activities [8,9]. This multitalented applicability of Imidazole draws attention towards the importance of access to efficient synthetic routes to well-designed and highly substituted imidazole derivatives.
Due to their potential utility, majority of these synthetic routes experience one or more severe disadvantages, such as difficult and intricate work-up and purification, huge amounts of waste materials, strongly acidic conditions, occurrence of side reactions, low yields, high temperature, long reaction time and the use of expensive reagents. Hence, there is a great demand of a highly efficient protocol with mild reaction conditions to synthesize substituted imidazoles.
In recent times, metal nanoparticles are used as heterogeneous catalysts in organic synthesis mainly because they achieve the objectives of green and sustainable chemistry. Recently Scientists have done a lot of work to synthesize precise metal nanoparticles. The new path is the coherent design and synthesis of very active and selective nanocatalysts by controlling the structure and composition of the active nanoparticles among all of them. The easiness of separation, recovery, and reuse of these NPs further enhance their attractiveness as green and sustainable catalysts [3,[34][35][36][37][38][39][40][41][42][43][44][45].
In view of the above and as a part of our research group to synthesize the biologically active compounds [68][69][70][71][72], it was thought worthwhile to synthesize some novel imidazoles fused with indole nucleus of biocidal interest because the combination of two or more different heterocyclic compounds in a single molecule frequently increases the biocidal profile amazingly. With the aim of getting targeted products, i.e., substituted imidazole a greener "NOSE" (nanoparticles-catalyzed organic synthesis enhancement) approach has been designed under solvent-free conditions.

Results and discussion
Imidazole derivatives 4a-s was synthesized by one pot multicomponent reaction of isatin derivatives 1a-g with ammonium acetate 2 and substituted benzaldehydes DOI: http://dx.doi.org/10.5772/intechopen.82720 3a-f in the presence of catalytic amount of ZrO 2 NPs under solvent-free conditions at 110°C, in good to excellent yields (Scheme 1).
To optimize the reaction conditions, several parameters were tested. The catalytic efficiency of the ZrO 2 NPs was highly influenced by their amount (mol%). Therefore, a model reaction of isatin with ammonium acetate and benzaldehyde using different amounts of ZrO 2 NPs was carried out ( Table 1). It has been observed that there is a notable impact of the catalyst on the yield of product and in the absence of catalyst only poor yield was obtained after 120 min (Entry 1, Table 1). It was found that product yield is increased with increasing catalyst concentration. Only 5 mol% of catalyst was required to provide 60% yield in 60 min (Entry 2, Table 1). The best yield of 88% was obtained with 15 mol% of ZrO 2 NPs (Entry 5, Table 1). However, the reaction rate and product yield were not improved by further increase of catalyst concentration (>15 mol%) (Entry 6, Table 1).
To optimize the molar proportion of the reactant, the model reaction was carried out using different molar proportions of reactants ( Table 2). A scrutiny of the table clearly shows that the best result was obtained using isatin, ammonium acetate, benzaldehyde in the molar proportion 1.0:5.0:1.0 at 110°C under solvent free conditions (Entry 5, Table 2).
To see the effect of temperature, the model reaction was examined under different temperatures. Obviously, reaction rate and product yield both were increased with enhancing temperature from 50 to 110°C. This study shows that the 110°C was favorable temperature for the multicomponent reaction of isatin with ammonium acetate and benzaldehyde ( Table 3).
Screening of solvent showed that solvent had a remarkable impact on the yield of product. It was observed that polar solvent provided better yield than nonpolar solvent, but excellent yield was obtained without solvent in smaller time. This may be due to the competitive adsorption of the solvent with the substrate molecule on the catalyst surface; hence reaction under solvent-free conditions gives excellent yield in short reaction time (Entry 5, Table 4). Another reason is that the eutectic mixture having uniform distribution of the reactants brings the reacting species in close proximity to react in solvent free condition than in the presence of solvent (Entry 1-4, Table 4).
Under the optimized set of reaction conditions, the effect of type of ZrO 2 (nano or bulk) was also examined using model reaction. (Table 5) This important parameter was studied by using four concentrations 5, 10, 12 and 15 mol% of ZrO 2 . These data proved that particle size and surface area would be an important factor for the catalytic efficiency of the ZrO 2 NPs.
The efficiency of the catalytic activity of the ZrO 2 NPs with several other catalysts was compared and is summarized in Table 6. The result indicates that ZrO 2 NPs was the best catalyst in terms of mol%, reaction time and percentage yield ( Table 6).
Under the optimized reaction condition, the scope of this methodology was extended to the reaction of different isatin with a wide range of aromatic aldehydes. The findings reveal that the proposed methodology is equally applicable for the presence of both electron donating as well as electron withdrawing groups at the 5-position of isatin moiety ( The model reaction was carried out to examine the reusability of the catalyst, After each reaction, catalyst was recovered by filtration, washed, air-dried and reused directly for the next time up to run no. 10.The results showed that there is no obvious loss in product yield in subsequent reuse which proves the reusability and recyclability of ZrO 2 NPs (    The following mechanism was proposed for the formation of substituted imidazoles catalyzed by the ZrO 2 NPs is given in Scheme 2. The reaction proceeds via the diamine intermediate [X]. Condensation of diamine with isatin derivatives followed by dehydration, and then rearrangement through the imino intermediate [Y] yielded the desired product.    ZrO 2 NPs were prepared and characterized by FTIR, XRD, SEM and TEM analysis. The BET surface area analyzer was used to calculate the specific surface area of synthesized ZrO 2 NPs. The molecular nature of the synthesized material was identified by the FT-IR spectrum of the ZrO 2 sample. The FT-IR spectrum of ZrO 2 NPs depends on the nature of the material, preparative procedures used, solid-state structure, and so forth. In FT-IR, a strong absorption peak at about 500 cm −1 region is due to the Zr-O vibration, which confirm the formation of ZrO 2 structure while the peak at 751 cm −1 is due to stretching vibrations of Zr-O-Zr, prominent peak at1340 cm −1 represents O-H bonding, peak at 1622 cm −1 perhaps owing to the adsorbed moisture and peaks at about 2855-2922 cm −1 region is due to stretching of O-H groups. The broad peaks with high intensity in XRD pattern of ZrO 2 NPs indicates that the sample was highly crystalline. The peaks observed at 2θ = 24.2 (011), 28.    . 79-1769). The broadening of peaks shows the smaller particle size of ZrO 2 NPs (Figure 1).
Morphological studies were done with the help of SEM and TEM analysis of 600°C calcinated ZrO 2 NPs sample that are shown in Figures 2 and 3, respectively. SEM analysis shows that NPs are non-homogenous and agglomerated and it also indicates the spherical nature and nano size (nm regime) of the ZrO 2 nanoparticles   Eco-Friendly and Facile Synthesis of Substituted Imidazoles via Nano Zirconia Catalyzed… DOI: http://dx.doi.org/10.5772/intechopen.82720 but size could be finely decided from TEM. For the purpose, TEM of sample has been shown in Figure 3.
As it is clear from TEM micrograph of sample, some agglomeration of the NPs, has been seen due to presence of different m-and t-phases in the sample. It was also observed that the sizes of the particles are of the order 20 nm along with agglomeration.
BET surface area analyzer was used to calculate the surface area of synthesized ZrO 2 NPs by nitrogen absorption which was found to be 44. 70 m 2 /g.

Typical procedure for the synthesis of ZrO 2 NPs
0.075 M solution of ZrOCl 2 .8H 2 O was prepared and then precipitated with NH 4 OH (25%) with continuous stirring on a magnetic stirrer till the P H raises in the range of 10-10.5.This resulted in the formation of precipitate of zirconium hydroxide. The precipitate was filtered and washed with double distilled water until traces of chloride ion were completely removed from the filtrate. Complete removal of chloride ion from filtrate was checked by titrating it with AgNO 3 solution using potassium chromate as indicator. Now, the precipitate was dried in oven at 80-90°C for 24 h and calcinated at 600°C for 3 h in order to formation of white nano zirconia powder.

General procedure for the synthesis of substituted imidazoles 4a-s
To a mixture of isatin derivatives 1a-g (1 mmol), ammonium acetate 2 (5 mmol), substituted aromatic aldehydes 3a-f (1 mmol), 15 mol% of ZrO 2 NPs was added (Scheme 1). The mixture was heated and stirred at 110°C for 30 min. The progress of the reaction was monitored by thin layered chromatography (n-hexane:ethyl acetate, 1:1). After completion, 20 ml acetone was added to the reaction mixture; the catalyst was removed by filtration and washed with xylene and acetone. Then, 50 ml of double distilled water is added to the liquid portion. This resulted in the formation of precipitate of products 4a-s. The precipitate was filtered, dried and recrystallized with ethanol.

Author details
Sundaram Singh* and Shivam Bajpai Indian Institute of Technology (BHU), Varanasi, India *Address all correspondence to: sundaram.apc@itbhu.ac.in