Facile Synthesis of 1,2-Disubstituted Benzimidazoles Using p -Toluenesulfonic Acid through Grinding Method
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acile Synthesis of 1,2-Disubstituted Benzimidazoles Using p-Toluenesulfonic Acid through Grinding Method C. Kathinga, N. G. Singha, J. World Star Rania, R. Nongruma, and R. Nongkhlawa,* a
Centre for Advanced Studies in Chemistry, North-Eastern Hill University, Shillong, Meghalaya, 793022 India *e-mail: [email protected] Received March 18, 2020; revised March 29, 2020; accepted March 31, 2020
Abstract—An efficient synthetic method for the highly selective synthesis of pharmacologically active 1,2-disubstituted benzimidazole derivatives from o-phenylenediamine and various aromatic aldehydes catalyzed by p-toluenesulfonic acid through grinding under solvent-free condition is described. The reaction requires the catalyst only during the conversion of intermediate N,N′-dibenzylidene-o-phenylenediamine into the desired product. The products were obtained within a short time with good yields by using only a mortar and pestle, which makes the proposed method convenient and cost-effective. Keywords: 1,2-disubstituted benzimidazole, p-toluenesulfonic acid, solvent-free reaction
DOI: 10.1134/S1070428020090201 INTRODUCTION In the field of medicine, compounds containing a benzimidazole nucleus have been termed as “privileged structures” for drug design owing to their broad spectrum of biological activity [1]. Benzimidazole derivatives exhibit diverse pharmacological properties such as antihistamine [2, 3], antidiabetic [4], chemotherapeutic [5], antiparasitic [6, 7], antiproliferative [8], anti-HIV [9, 10], anticonvulsant [11], antineoplastic [12, 13], DNA binding agent [14], enzyme and receptor agonists or antagonists [15]. In addition, they have found applications in veterinary medicine as anthelmintic agents and have been used as organic ligands [16, 17], fluorescent whitening agents [18] and functional materials [19]. The synthesis of 1,2-disubstituted benzimidazole derivatives has been extensively studied, as evident from the growing number of publications. Despite the numerous records available it has been still explored rapidly due to its high profile of biological applications. General methods for the preparation of 2-substituted benzimidazole derivatives involve the condensation of o-phenylenediamines with carboxylic acids or their derivatives (nitriles, imidates, or ortho esters) in the presence of various acid catalysts [20–22]. The classical methods for the synthesis 1,2-disubstituted benzimidazole include N-alkylation of 2-substituted benzimidazole using a strong base [23, 24], reductive
cyclization with o-nitroaniline and aldehydes [25, 26], cyclocondensation of N-substituted o-aminoanilides [27, 28], and condensation of N-substituted phenylenediamines with α-hydroxybenzylsulfonic acid sodium salt [29]. However, the most common method to access 1,2-disubstituted benzimidazoles is based on the direct coupling of o-phenylenediamines with aromatic aldehydes in the presence of acid catalysts [30–36]. The series of catalysts that have been used for the synthesis of 1,2-disubstituted benzimidazoles includes trime
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