Synthesis of N-Arylimidazole Derivatives From Imidazole and Arylhalides in the Presence of Recoverable Pd/AlO(OH) NPs

Synthesis of N-Arylimidazole Derivatives From Imidazole and Arylhalides in the Presence of Recoverable Pd/AlO(OH) NPs. This study reveals the synthetic method for preparation of the N-arylimidazole derivatives with commercially available aluminium oxy-hydroxide-supported palladium (Pd/AlO (OH)) nanoparticles. The expected products were achieved with high yields in a mixture of H 2 O/IPA (v/v=1/1) under ultrasonic conditions. It is a province in the literature as the catalyst and application area used. The isopropyl alcohol was used as a support for water for solubility, and reactions were carried out in an environmentally friendly solvent medium. The catalyst purified from the reaction medium was used repeatedly without losing its effectiveness. The method developed for the synthesis of N-arylimidazole derivatives; is an environmentally friendly, economical and highly available method.


Introduction
N-arylimidazole derivatives are molecules that have biological activity and have an important place in scientific studies in recent years. The scientists focused on the synthesis of natural and unnatural N-arylimidazole derivatives to examine the intercourse between biological activity and molecular structure [1,2].
Heterocyclic imidazole derivatives such as Liarozole, Alcaftadine and Zolpidem, which are shown in Figure 1, form the active ingredient of many drugs and are known to be vital with their effects.
Liarozol has been demonstrated to inhibit cytochrome P450 (CYP) enzymes that perform retinoic metabolism in the body, thereby revealing the body's retinoic acid synthesis and its therapeutic effect as in synthetic retinoids. Retinoic acids not only support the normal growth of the body, but also play an important role in the differentiation of epithelial cells [3]. Alkaftadine has a therapeutic effect especially on the outermost layer of the eye resulting from an allergic reaction [4]. Zolpidem is used as an active ingredient of drugs used in anxiety and insomnia problems (Scheme 1) [5]. In recent years, the use of heterogeneous catalysts in classical reactions such as hydrogenation [6,7] and coupling [8,9] has become the focus of attention by scientists. Especially the use of single metal containing (monometallic) transition metal nanoparticles as well as two metal containing (bimetallic) nanoparticles as a heterogeneous catalyst creates a more advantageous situation in terms of reaction conditions.   [21] and azido compounds [22] and in the knoevenagle condensation [23] dehalogenation of aryl halides [23] and in the oxidation of benzylic alcohols [24]. Herein, the formation of N-aryl imidazoles was carried out using ultrasonic conditions and PdAlO (OH) NPs, which is highly stable and reusable in eco-friendly solvent mixture such as H 2 O / IPA.

Experimental Materials
All reagents (imidazoles, aryl halides, catalyst, potassium hydroxide) and solvents were provided from Sigma-Aldrich and used without further purification.

Characterization Methods
1H/13C NMR spectra were recorded on a Jeol ECS 400 MHz spectrometer.
General Procedure for the Synthesis of N-Arylimidazoles

Results and Discussion
The Scanning Electron Microscopy (SEM) and x-ray diffraction (XRD) ( Figure S1) analysis of the catalyst was taken before the synthesis of N-aryl imidazole derivatives and after the same reaction was repeated five times. As seen in irregularly spreading    Table 2 showed that the commercially available Pd/AlO(OH) catalyst was tested in the synthesis of N-aryl imidazole derivatives. In this reaction, aryl halides and imidazole derivatives were preferred as the starting material. N-phenyl imidazole (2) and 1-(4-nitrophenyl)-1H-imidazole (6) compounds were obtained using different aryl halides. In this study, the effects of the groups -Cl, -Br and -I were compared as the leaving group. As expected, iodine benzene (4) reacted with higher yields to obtain related products ( Table 2, entries 1-6). 1-(4-Bromophenyl)-4-nitro-1H-imidazole (10) was obtained in low yields. Because, the nucleophilic feature is weakened due to the -NO 2 group, which is the electron attracting group in the imidazole structure used as the starting material ( Table 2,  As expected, aryl halides containing nitro groups turn into products with higher yields (  The literature information related to the synthesis of N-phenyl imidazole is given in Table 4. The use of different types of heterogeneous catalysts in N-arylation reactions appears to have some advantages: high yield synthesis of products, recovery of catalysts and repeated use. However, it is an important problem that the reaction times are long and the reactions are carried out at high temperatures. Table 4 shows that copper-containing heterogeneous catalysts are used in N-arylation reactions. However, since the catalysts containing copper are unstable, the catalyst structure deteriorates under atmospheric conditions and the transition of the metal to the reaction medium is an environmental threat. Therefore, the repeated use of copper-containing catalysts is very weak. However, the catalyst we use in this study is stable under different atmospheric conditions and has a feature that can be used many times by being easily removed from the reaction medium.
Of course, in the literature, heterogeneous catalysts containing palladium are also used in N-arylation reactions. However, as seen in Table 1, long reaction times and high temperatures are a major disadvantage in terms of time and energy economy.

Scheme 2:
The possible mechanism for the N-aryl imidazole derivatives.

Conclusion
In summary, a new method has been developed for the synthesis of N-aryl imidazole derivatives with high yields and short periods using Pd/AlO(OH) NPs in ultrasonic conditions. The use of the relevant catalyst in coupling reactions is a first in the literature.
The use of a second solvent, such as isopropyl alcohol, which will support the solubility of imidazole derivatives and aryl halides, as the starting materials, increases the solubility and makes the reaction easily. In addition, after the reaction, the catalyst was gained and used again and again. The rate of metal that has passed into the solvent after their reuse was determined with ICP-MS. The method we developed is an alternative for environmentally friendly, economical and docking reactions.