Recent Developments Towards Synthesis of (Het)arylbenzimidazoles

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

Working in the Dark

Three turns of the Calvin cycle (Figure 11.1), allow the conversion of three (3) equivalents of carbon dioxide (CO2) (i.e., 3 C1 units) along with three (3) equivalents of the five-carbon carbohydrate derivative, ribulose-1,5-bisphosphate (i.e., 3 C5 units) to yield three (3) not yet isolated six-carbon adducts, 2-carboxy-3-ketoribitol-1,5-bisphosphate (3 C1 + 3 C5 = 3 C6) to form. The three (3) C6 species then undergo fragmentation to yield six (6) equivalents of the three (3) carbon dihydroxy monocarboxylate, 3-phosphoglycerate (i.e., 3 C6 = 6 C3). A cartoon representation of this process is shown in Scheme 11.1 for one of the three CO2 units. Of the six (6) three-carbon unit equivalents, five (5) are used to regenerate three (3) equiv¬alents of ribulose-1,5-bisphosphate (i.e., 5 C3 = 3 C5), while the sixth three- carbon fragment is now available to combine with another to make a six (6) carbon sugar (2 C3 = 1 C6) such as glucose (C6H12O6) (Figure 11.2). Additionally, as shown in Figure 11.3, 3-phosphoglycerate can be used to make other small compound building blocks such as glyceric acid, lactic acid, pyruvic acid and even acetic acid (after decarboxylation). Ribulose- 1,5-bisphosphate (often abbreviated as RuBP), using the enzyme ribulose- 1,5- bisphosphate carboxylase (EC 4.1.1.39, carboxydismutase, rubisco), catalyzes the Mg2+- dependent conversion of the 1,5- bisphosphate ester of the carbohydrate ribulose with carbon dioxide (CO2) to produce two (2) equivalents of 3- phosphoglycerate (PGA). As shown in the Schemes 11.1 and 11.2. A hypothetical the six carbon intermediate, 2- carboxy- 3- ketoribitol- 1,5- bisphosphate, is often written. It is important to keep in mind that we want the 3- phosphoglycerate for purposes of construction of other important compounds. But, as noted above, three turns of the cycle are necessary to produce six (6) equivalents of 3- phosphoglycerate, and five (5) of them are reused in making the three (3) ribulose- 1,5- bisphosphates necessary to turn the cycle three (3) times.