A General Approach to Substituted Benzimidazoles and Benzoxazoles via Heterogeneous Palladium‐Catalyzed Hydrogen‐Transfer with Primary Amines

Abstract

The synthesis of benzimidazoles starting from o-phenylenediamines and amines in the presence of palladium on charcoal as catalyst is reported. Under microwave dielectric heating it is possible to use a tertiary, a secondary, and even a primary amine as the substrate for a palladium-mediated process to get 2-substituted or 1,2-disubstituted benzimidazoles, depending on the nature of the o-phenylenediamine employed. Primary amines are the most suitable reagents for the atom economy of the overall process that resulted to be general as several different substituted benzimidazoles were obtained in good yield. Benzoxazoles can be also prepared starting from primary amines and o-aminophenol. The reaction is also highly selective as no (poly)-alkylated pheny-A C H T U N G T R E N N U N G lenediamines or cross-contaminated benzimidazoles are obtained starting from N-monoalkylphenylenediamines. This behavior was interpreted as a scarce aptitude to dehydrogenation of the methylene bonded to the aromatic NH of N-alkylarylamines. The experiments carried out consent to draw an almost complete picture of the reaction pathways occurring during the process. The catalyst can be recycled several times and, although far from optimal performances, catalyst TON = 90 is encouraging for further large-scale optimization protocols. In addition, the palladium on charcoal-catalyzed microwave-assisted reaction of o-phenylenediamine gives de-alkylation of tertiary amines and transformation into the secondary ones.

Iron(ii) bromide-catalyzed oxidative coupling of benzylamines with ortho-substituted anilines: synthesis of 1,3-benzazoles

“…13d Narender et al15a and Nguyen et al 15b,c independently reported a few metal-free procedures for synthesis of benzimidazoles and benzothiazoles from benzylamines and 2-amino/mercaptoanilines. Scheme 1c).…”

Avoiding hot-spots in Microwave-assisted Pd/C catalysed reactions by using the biomass derived solvent γ-Valerolactone

“…With this promising data in hand, we have also found that by using 0.35 equivalents of Et 3 N there was no impact on the conversion (Fig. 2 , entry 2), proving that two of the three groups of the tertiary amine could be transferred to 1a 25 . Similar results were obtained irradiating for 60, 30 or even only 20 minutes (Fig.…”

“…2 , entry 6) or using toluene as the solvent for 90 minutes (Fig. 2 , entry 7) 25 lower conversions were observed. Irradiation of 1a in GVL led to good reaction yields also when the catalyst amount was reduced to 5 or even 2.5 mol% (Fig.…”

“…In the context of using MWs for effective synthesis of natural products and pharmaceutically relevant ingredients 64 – 67 , we have faced a specific issue in the route towards the definition of an efficient protocol for the MW-assisted, Pd/C catalysed one-pot synthesis of polyfunctionalized benzimidazoles by a hydrogen transfer reaction 25 . The developed protocol takes advantages from MWs and Pd/C interaction, while the reaction does not proceed at all under traditional heating using the same catalyst and conditions.…”

Pd/C Catalysis under Microwave Dielectric Heating

“…The reaction occurred in toluene under MW dielectric heating with crotonitrile as a hydrogen acceptor, allowing the direct transformation of tertiary amines into benzimidazoles [95]. Primary amines (such as 131 in Scheme 38) can also be used in the presence of acetic acid as an additive in a synthesis of 1(H)-benzimidazoles, 1-susbtituted benzimidazoles, and benzoxazoles (such as 133 in Scheme 38) [96]. The possibility of oxidizing amine to imines has also been exploited in the synthesis of heterocycles through an overall hydrogen transfer oxidative process.…”