Recent Developments Towards Synthesis of (Het)arylbenzimidazoles

Abstract

Benzimidazole is an important heterocycle that is widely researched and utilized by the pharmaceutical industry and is one of the five most commonly used five-membered aromatic heterocyclic compounds approved by the US Food and Drug Administration. In view of their wide-ranging bioactivities, systems containing benzimidazole as one of the moieties occupy a special place among other benzimidazole derivatives. Since 2010, many improved synthetic strategies have been developed for the construction of hetaryl- and arylbenzimidazole molecular scaffolds under environmentally benign conditions. This review emphasizes the recent trends and modifications frequently used in the synthesis of derivatives of benzimidazole such as the Phillips–Ladenburg and Weidenhagen reactions, as well as entirely new methods of synthesis, involving oxidative cyclization, cross-coupling, ring distortion strategy, and rearrangements carried out under environmentally benign conditions.1 Introduction2 From 1,2-Diaminobenzenes with Various One-Carbon Unit Suppliers2.1 Phillips–Ladenburg Reaction2.1.1 With (Het)arenecarboxylic Acids2.2.2 With (Het)arenecarboxylic Acid Derivatives2.2 Weidenhagen Reaction2.2.1 With (Het)arenecarbaldehydes or (Het)aryl Methyl Ketones2.2.2 With Primary Alcohols2.2.3 With Primary Alkylamines2.2.4 With 2-Methylazaarenes2.2.5 With Other One-Carbon Fragment Suppliers3 From 2-Haloacetanilides and Amines4 From Amidines5 From Tetrahydroquinazolines6 Mamedov Rearrangement7 Conclusions and Outlook

The Highly Efficient Synthesis of 1,2-Disubstituted Benzimidazoles Using Microwave Irradiation

“…The products were isolated after organic phases dried over Na 2 SO 4 , followed by evaporation under reduced pressure. Spectral data were in accordance with the literature [ 72 , 73 , 74 ]. See Supplementary Materials .…”

Highly Efficient Synthesis of Benzimidazoles Using Microwave Irradiation

“…The products were isolated after organic phases dried over Na2SO4, followed by evaporation under reduced pressure. Spectral data were in accordance with the literature [87].…”

Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents

“…The synthesis of three types of new regioisomeric derivatives of 2-(benzimidazol-2-yl)­quinoxaline 13 and 14 containing, in position 6 or 7, 4-methylpiperazine, 4-phenylpiperazine (Table , entries 1–5 and 6) (type I), piperidine (Table , entries 7 and 8) (type II), and morpholine (Table , entries 9 and 10) (type III) fragments, was carried out via Mamedov rearrangement − by the interaction of 3-aroylquinoxalinones 9a – 9f with benzene-1,2-diamines 12a – 12d at reflux in acetic acid for 4 h. Along with the target products 13ea, 14ea (Table , entry 5) and 13ed , 14ed (Table , entry 10), byproducts 15ea , 16ea and 15ed , 16ed are formed, respectively (Figure ), as a result of nucleophilic substitution of the fluorine atom of the aryl ring with the nitrogen atom of the benzimidazole system; , mixtures of regioisomers 15ea / 16ea and 15ed / 16ed were isolated by column chromatography. The structures of compounds 13da and 14da were confirmed by the single-crystal X-ray analysis (Figure ), and the phase state of a powder mixture of these regiosomers was analyzed by powder X-ray diffraction (see Supporting Information).…”

“…To check these binding interactions and antitumor activity of a novel series of regioisomeric 2-(benzimidazol-2-yl)-3-arylquinoxalines designed using a concept of molecular hybridization with the mentioned substituents in positions 6 and 7 of the benzene ring of the quinoxaline system, we studied the reactivity of 3-aroylquinoxalinones with respect to specially synthesized benzene-1,2-diamines with N -methyl, N -phenylpiperazine, piperidine, and morpholine substituents in position 4 of the benzene ring under Mamedov rearrangement − conditions.…”