1.2- Disubstituted-benzimidazoles

Jacob et al. [22] presented an improved green solvent free methodology for the selective synthesis of 1,2-disubstituted benzimidazoles (xiii) by the condensation of o-phenylenediamine and aldehydes using solid-supported catalyst (Si02/ZnCl2). 

Su et al. [35] gave the mercury (ll)-catalyzed liquid phase synthesis of 1,2-disubstituted benzimidazoles (xxviii) by utilizing SnAt reactions, reduction and cyclization reaction. Tbe yield of the product ranged between 73-90%. 

There have been a number of studies of the behaviour of benzimidazolium species with nucleophiles, and ring opening is especially easy when there is a l-(2,4-dinitrophenyl) substituent. Even weak bases such as aniline or pyridine can effect the transformations. Under the influence of benzoyl chloride in aqueous alkali, 1,2-disubstituted benzimidazoles are cleaved in a rather complex reaction. Provided that a methylene or methyl group is present at C-2, compounds of type (110) result (Scheme 49) (74CRV279). 

The reaction between o-phenylenediamine and an equimolar amount of an aromatic or heterocyclic aldehyde has been shown to proceed by initial formation of a monoanil (74). In the presence of oxidizing agents (e.g. nitrobenzene, which also acts as the solvent) this can form the 2-substituted benzimidazole. With two moles of aldehyde the bis-anil (75) forms, giving rise to a 1,2-disubstituted benzimidazole (Scheme 42). This aldehyde route to benzimidazoles is particularly suited to the synthesis of compounds with a heterocyclic group (e.g. 2-thienyl-, 2-pyridyl-) at C-2. Reaction of 2,2,4,4-tetrakis(trifluoromethyl)-l,3-dithietane with o-phenylenediamine gives 2,2-bis(trifluoromethyl)benzimidazoline (7430785). 

The reductive cyclization of acylated o-nitroanilines (31) is a highly versatile process, since variation of both arylaminc and acyl portions can lead to a wide variety of products. Thus, an acylated )V-alkyl-o-nitroaniline gives a 1,2-disubstituted benzimidazole an acylated o-nitrodiarylamine will lead... 

Likewise, the oxidative C-H amination of A -aryl-A -tosyl/A -methylsulfonylamidines and N,N -bis(aryl)amidines has been accomplished using iodobenzene as a catalyst to furnish 1,2-disubstituted benzimidazoles in the presence of mCPBA as a terminal oxidant at room temperature (Scheme 4.25) [51]. The reaction is general and the target benzimidazoles can be obtained in moderate to high yields. 

A synthesis of 1,2-disubstituted benzimidazoles has been reported (Scheme 42). iV-Bromosuccinimide has been reported to promote ring expansion of lactam-tethered aUenols to give cyclic a- or -ketoamides with high chemo-, regio-, and diastereo-selectivity through controlled C—C bond cleavage of the or y-lactam nucleus (Scheme 43). 

Paul, S. and B asu, B. 2012. Ffighly selective synthesis of libraries of 1,2-disubstituted benzimidazoles using silica gel soaked with ferric sulfate. Tetrahedron Lett. 53(32) 4130-4133. 

Wan JP, Gan S-F (2009) Water mediated chemoselective synthesis of 1,2-disubstituted benzimidazoles using o-phenylenediamine and the extended synthesis of quinoxalines. Green Chem 11 1633 1637... 

Chebolu R, Kommi DN et al (2012) Hydrogen-bond driven electrophilic activation for selectivity control the scope and limitations of fluorous alcohol promoted selective formation of 1,2-disubstituted benzimidazoles and mechanistic insight for rational of selectivity. J Org Chem 77 10158-10167... 

Santra S, MajeeA, HajraA(2012)Nano indium oxide an efficient catalyst for the synthesis of 1,2-disubstituted benzimidazoles in aqueous media. Tet Lett 53 1974-1977 Deobald AM, Camargo LRS, Alves D, Zukerman-Schpector J, Corre AG, Paix ao MW (2011) Click chemistry an efficient synthesis of heterocycles substituted with steroids, sapo-nins, and digitalis analogues. Synthesis 24 4003-4010... 

The synthesis of 2-substituted-benzimidazoles 61 and 1,2-disubstituted-benzimidazoles 63 from o-phenylenediamines 60 and 1,2-disubstituted-benzenes 62, respectively, are shown in the tables given below. 

Transition-metal-catalyzed methods were utilized in the preparation of 2-substituted benzimidazoles. Oxidative C-H amination of arylamidines 64 provided access to 1,2-disubstituted benzimidazoles 65 in the presence of MCPBA as a terminal oxidant (130L1334). 1,2-Disubstituted benzimidazoles were synthesized using microwave-assisted solid phase with a phos-phonium linker (13JHC720). 

In order to investigate the further application of immobilized 4-fluoro-3-nitro benzoic acid synthon, we expanded our methodology to prepare 1,2-disubstituted benzimidazoles 23-25. Figure 11 shows our detailed efforts toward the preparation of a benzimidazole library. To achieve this goal, one pot cyclization of PEG-bound diamine 12 with trimethylorthoformate in TEA/... 

Disubstituted benzimidazoles 10 are also obtained by Cu-mediated amination of (2-acylamino)aryl iodides with arylamines in the presence of L-proline and K2CO3 followed by add-catalyzed cydization [417]. 

One-pot S5mthesis of both 1,2-disubstituted benzimidazoles and quinoxalines has been carried out in water at room temperature with excellent yields [69]. In the presence of trimethylsilyl chloride, o-phenylenediamine gives benzimidazole with aldehyde and quinoxaline with a-bromoketone. Isotope-labeling experiment carried out in the reaction with benzaldehyde and o-phenylenediamine demonstrated the 1,3-hydride migration process during the formation of 1,2-disubstituted benzimidazoles (Scheme 47). 

Disubstituted benzimidazoles could be obtained from arylcarbodiimides in moderate to good yields under Cu(0Ac)2/02 system at 100 °C in one-pot cascade procedure (Scheme 8.53). This copper-catalyzed efficient 1,2-disubstituted benzimidazoles synthesis includes C-H activation/C-N or C-O bond formation. The nucleophiles involve various A/ -nucleophiles and 0-nucleophiles such as amine and alcohol. Electron-donating groups on the arylcarbodiimides accelerate this reaction in contrast to the electron-withdrawing groups [93]. 

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