Abstract
A novel method for synthesis of tricyclic benzimidazole derivatives by using continuous flow reactor is reported. Disadvantages of the well-known batch methods have been avoided utilizing the flow chemistry technology. Beside the one pot reductive cyclization using H-Cube Pro®, the dehydration step was also optimized producing the desired lactam compounds. Then the acylation was optimized under microwave conditions and that reaction was also integrated into the flow system using an Asia heater module. This acylation dramatically reduced the reaction time under continuous-flow conditions, with a residence time of 30 min.
Highlights
Nitrogen containing bi- and tricyclic heterocyclic compounds bearing benzimidazole and pyrrolobenz-imidazole moieties are in the focus of the drug discovery interest, because of their comprehensive pharmacological applications
Continuous flow hydrogenation reactions were performed on an H-Cube Pro® flow system, utilizing water electrolysis to generate hydrogen
Based on the results we concluded, that the residence time has no effect on product selectivity and 2-(1H-benzo[d]imidazol-2-yl)alkanoic acids (7, 8) can be produced with good selectivity (94 %, Table 1)
Summary
Nitrogen containing bi- and tricyclic heterocyclic compounds bearing benzimidazole and pyrrolobenz-imidazole moieties are in the focus of the drug discovery interest, because of their comprehensive pharmacological applications. In order to highlight the need for a new synthetic procedure, we review the major procedures reported in literature taking 2,3-dihydro-1H-pyrrolo[1,2-a]benz-imidazole-1-one (1) as model compound. First step is the acylation at 100 °C and the water elimination is carried out on a higher (~180 °C) temperature reaching a relatively low overall yield (38 %) [7]. Another procedure is a solid-state condensation catalyzed by Lewis acid (zinc(II)acetate) using extremely high temperatures (from 220 to 300 °C) [8]. The ring closure can be carried out via NH2 R
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