Copper-Catalyzed One-Pot Synthesis of Substituted Benzimidazoles (original) (raw)
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Copper-Promoted One-Pot Approach: Synthesis of Benzimidazoles
Molecules
A facile, one-pot, and proficient method was developed for the production of various 2-arylaminobenzimidazoles. This methodology is based for the first time on a copper catalyst promoted domino C–N cross-coupling reaction for the generation of 2-arylaminobenzimidazoles. Mechanistic investigations revealed that the synthetic pathway involves a copper-based desulphurization/nucleophilic substitution and a subsequent domino intra and intermolecular C–N cross-coupling reactions. Some of the issues typically encountered during the synthesis of 2-arylaminobezimidazoles, including the use of expensive catalytic systems and the low reactivity of bromo precursors, were addressed using this newly developed copper-catalyzed method. The reaction procedure is simple, generally with excellent substrate tolerance, and provides good to high yields of the desired products.
Benzimidazoles were synthesized by the copper-catalyzed, one-pot, three-component reaction of 2haloanilines, aldehydes, and NaN 3 . The reaction was optimized when 2-iodo-or 2-bromoanilines (1.0 equiv), aldehydes (1.2 equiv), NaN 3 (2.0 equiv), 5 mol% of CuCl, and 5 mol % of TMEDA were reacted in DMSO at 120°C for 12 h. Good yields resulted, and the reaction showed tolerance toward functional groups such as ester, nitro, and chloro. Aliphatic and heteroaromatic aldehydes also afforded the desired products in moderate to good yields.
Angewandte Chemie International Edition, 2007
2-Disubstituted benzimidazoles are an important class of heterocyclic compounds that exhibit a wide range of biological properties. [1] Previous syntheses of 1,2-disubstituted benzimidazole structures not only led to drug leads such as the hepatitis C virus (HCV) NS5B polymerase inhibitor 1 [2] and the agonist 2 against the g-aminobutyric acid A receptor (GABA A), [3] but also resulted in commercial pharmaceutical products such as the antihypertensive telmisartan (3, Scheme 1). [4] Although 1,2-disubstituted benzimidazoles play an important role in pharmaceutical science, the available synthetic strategies that lead to these compounds are limited compared with those that lead to the structurally related indoles. The classical methods for the assembly of these molecules include acylation/cyclization processes from ortho-aminoanilines, [2] reduction/cyclization processes from ortho-nitroanilines, [5] and alkylation of 2-substituted benzimidazoles. [3, 6] The drawback of these procedures is the limited diversity of the available starting materials. In an attempt to circumvent this restriction, a metal-catalyzed intramolecular amination approach was recently reported. [7] However, the products are limited to the 2-aminobenzimidazoles. Herein, we report a new cascade process for the formation of 1,2-disubstituted benzimidazoles from 2-haloanilides and primary amines. In recent years, we have witnessed great progress in the development of mild Cu-catalyzed Ullmann-type reactions using N,N-, N,O-, and O,O-bidentate ligands. [8, 9] Several useful domino processes have been developed based on these investigations. [10] During studies on the CuI-catalyzed assembly of diaryl ethers using amino acids as ligands we discovered that there is an ortho-substituent effect directed by NHCOR groups in Ullmann-type C À O bond formations. [11] Further explorations revealed that the same effect exists in the coupling of aryl halides with activated methylene compounds. [12] We were interested in whether this effect could promote aryl amination to afford ortho-aminoanilides at low reaction temperatures, which in turn would provide 1,2disubstituted benzimidazoles through an intramolecular condensation. It is noteworthy that low reaction temperatures are essential for obtaining ortho-aminoanilides because orthohaloanilides can undergo the Cu-catalyzed cyclization at 80 8C to afford benzoxazoles. [13] With this idea in mind, we carried out the reaction of 2iodotrifluoroacetanilide (4 a) with benzylamine catalyzed by CuI/l-proline (Scheme 2). We were pleased to find that after 12 h at room temperature, 4 a was consumed to give a mixture of aniline 5 a (46 % yield) and benzimidazole 6 a (30 % yield). Since iodobenzene does not couple with benzylamine under the same conditions, [9f, h] the formation of 5 a and 6 a clearly demonstrate that the ortho-NHCOCF 3 group promotes the amination. We then tried to transform 5 a into 6 a in a one-pot reaction, and found that 6 a was formed exclusively when the Scheme 1. Structures of pharmacologically important 1,2-disubstituted benzimidazoles. Bn = benzyl. Scheme 2. Coupling of 4 a with benzylamine catalyzed by CuI/l-proline. DMSO = dimethyl sulfoxide.
Selective Synthesis of 2-Aryl-1-benzylated-1H-benzimidazoles
Chinese Journal of Chemistry, 2011
An efficient and simple procedure was developed for the green synthesis of various 2-aryl-1-benzylated-1H-benzimidazoles in high yields by condensation of o-phenylenediamine with aldehydes with P 2 O 5 /SiO 2 as catalyst under solvent-free and ambient conditions.
A one-pot tandem synthesis of various 1,2-disubstituted benzimidazoles
Tetrahedron Letters, 2014
A facile method to synthesize various 1,2-disubstituted benzimidazoles is developed. It is suggested that formation of a Meisenheimer adduct between the substrate, amine and solvent aids the N-arylation process. The generality of the protocol is demonstrated by the efficient reactions involving numerous substituents ranging from electron-withdrawing groups to electron-donating groups.