Synthesis Of Benzimidazole-Fused Heteroarenes Via Palladium-Catalyzed C-H Functionalities

Benzimidazole-fused arenes are frequently found in a diverse array of compounds, including a wide range of significant natural products, biologically and therapeutically active compounds and functional materials. For examples, benzimidazole-fused isoquinoline frameworks are an important class of pharmacophores and many derivatives display a wide range of biological and therapeutical activities, such as anticancer, antimicrobial, anti-HIV-1and antifungal properties.1,2-(Hetero)aryl fused imidazoles or benzimidazoles, as electron-transporting and emission functional units, are prevalent in advanced organic materials. Hence, molecules containing this motif have attracted considerable attention in organic synthesis, medicinal and material chemisty, and much effort has been focused on the synthetic methods of benzimidazole-fused aromatic system.Part A:Synthesis of benzo[4,5]imidazo[2,1-a]isoquinolinesAn efficient "one-pot" route for the synthesis of benzo[4,5]imidazo[2,1-a] isoquinolines has been developed via nucleophilic addition of2-aryl benzimidazoles to alkynyl bromides and subsequent palladium-catalyzed intramolecular C-H vinylation. The first nucleophilic addition step was carried out in DMF at120℃using K2CO3as the base for2hours, giving (Z)-N-(1-halo-1-alken-2-yl)benzimidazoles. Upon treating the in-situ formed adduct with a mixture of Pd(OAc)2(5mol%), PCy3(15mol%) and K2CO3at130℃for16h, the desired cyclization took place providing benzo[4,5]imidazo [2,1-a]isoquinolines in good yields. With the optimized reaction conditions in hand, the scope and generality of the present process was then explored. A large range of benzo[4,5]imidazo[2,1-a] isoquinolines were prepared, and a proposed reaction mechanism was shown in the paper.Part B:synthesis of benzimidazole-fused phenanthridinesAn efficient palladium-catalyzed route for the synthesis of benzimidazole-fused phenanthridines from o-dibromoarenes and2-arylbenzimidazoles is described. The sequentially accomplished reaction comprises intermolecular C-H arylation of2-arylbenzimidazoles followed by an intramolecular N-arylation reaction promoted by the same Pd catalyst. Extensive experiments were conducted for a palladium-catalyzed twofold arylation of2-aryllbenzo[d]imidazoles and o-dibromoarenes as the coupling partners. Xphos or DPE-phos for Pd(OAc)2was found to be the best catalyst system to achieve benzimidazole-fused phenanthridines with K2CO3as a base in DMF at160℃for24h. The scope and generality of the present annulation process was then explored by testing a set of structurally diverse2-aryl benzimidazoles with1,2-dihalobenzene. To gain insight into the mechanism of the reaction, some designed control experiments were conducted, and a proposed reaction mechanism was shown. Finally, photophysical properties of benzimidazole-fused phenanthridines as fluorescent materials were studied in details.In conclusion, two new synthetic methods to benzimidazole-fused arenes have been developed. These protocols are not only a valuable addition to the tool box of the synthesis of hetero-polycyclic aromatic compounds, but also enrich the contents of palladium-catalyzed cascade cyclizations reactions, which should be of considerable interest of the valuable synthetic building blocks for medicinal and material science.