Functionalized 2-aryl benzimidazoles

Under oxidative or acidic conditions, or merely by heating the reagents, appropriately functionalized aryl-amidines or -guanidines cyclize to 1-alkyl or 1-aryl-benzimidazoles [51, 52]. If guanidines are employed. 

A particular case of a photochemical strategy towards functionalized benzimidazoles regards the synthesis of 2-acylamino derivatives 70, which can be obtained from irradiations in methanol of 3-(o-amino)phenyl-l,2,4-oxadiazoles 68. In this reaction, a photolytic cleavage of the ring O—N bond, followed by migration of the aryl substituent, leads to the carbodiimide intermediate 69, a precursor of the benzimidazole nucleus (Scheme 12.20) [47]. 

Functionalization of C - H bonds of heterocycles to C-arylation is an important synthetic reaction that is used to build important bioactive structures. Recently palladium and copper-mediated C-2 arylations of benzimidazole with aryl iodides under ligandless and base-free conditions have been described (Scheme 14) [56]. These reactions show complete selectivity under these conditions and allow for the use of substrates containing base-sensitive groups without their prior protection, such the NH group of benzimidazoles [56,57]. The aryl-substituted benzimidazole compounds were obtained in high purities and yields within 48 hours, and the scheme was also applicable to other azoles. 

Using a somewhat different C-H functionalization approach to benzimidazoles, Punniyamurthy and co-workers have explored the conversion of A -benzyl bisarylhydrazones to 2-aryl-A -benzyl-benzimidazoles. This conversion is optimally achieved using stoichiometric Cu(OTf)2 in toluene at 110 °C. (This transformation was also reported using catalytic Cu(OTf)2 (20 mol%) under an oxygen atmosphere, albeit in lower yield). This reaction likely proceeds via a copper-amidine intermediate analogous to the intermediate accessed by Brasche and Buchwald in their direct intramolecular arylation of iV-aryl amidines. 

Intermolecular direct arylations of heteroarenes, such as indoles, pyrroles or (benzo)furans, were, thus far, predominantly achieved with palladium catalysts (see Chapter 10). However, rhodium complexes proved also competent for the direct functionaUzations of various valuable heteroarenes with comparable or, in some cases, improved catalytic performance. Thus, rhodium-catalyzed C—H bond functionalizations of various N-heterocycles, were elegantly developed by Bergman, Ellman and coworkers. Here, the use of a catalytic system comprising [RhCl(coe)2]2 and PCys led to direct arylations of unprotected benzimidazoles with aryl iodides... 

A very different mechanism occurs in the arylation of benzoxazol, benzimidazol and related heterocydes via rhodium-catalyzed C—H bond functionalization (Scheme 11.25) [81]. Thus, this reaction proceeds by an initial coordination and... 

Chouhan et al. (2007) found that Cu(I)-catalyzed C-N coupling reactions between aryl/heteroaryl bromides and azoles could be efficiently facilitated by the proline-functionalized magnetic nanoparticles (MNPs). Generally, the desired A-aryl/A-heteroaryl azoles (including pyrazoles, indoles, and benzimidazoles) were synthesized in good to excellent yields (Scheme 4.27). 

Pyrido[l,2-u]benzimidazoles are prepared by hypervalent iodine C-H cycloamination of N-aryl-2-aminopyridines (Scheme 49) (13T10739).The reaction tolerated both electron-donating (OMe, Me, f-Bu) and electron-withdrawing groups (halides, nitro) on the aniline. However, sterics appears to slow the reaction as the yields were poor (9-23%) with same functional groups when placed ortho rather than para. A number of substituents (Me, halides, esters, CF3) were also tolerated on the pyridine ring. Quinolines and isoquinolines also reacted smoothly under these conditions. 

An efficient method for the transformation of N-benzyl bisarylhydrazones to functionalized 2-aryl-N-benzyl-benzimidazoles involving a Cu(ll)-mediated cascade C-H functionalization/C-N bond formation under neutral conditions was reported by Punniyamurthy et al. (Scheme 79) [19]. Substrates having either electron-donating or electron-withdrawing substituents undergo efficient cyclization. 

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