Sustainable Synthesis of Polyfluoro-Pyrimido [1,2-<i>a</i>] Benzimidazole Derivatives Using a Tandem Strategy─Ultrasound and an Integrated Continuous Flow System

We have developed a novel ultrasound technique that generates significant amounts of CF₃-substituted benzo[4,5] imidazo [1,2-<i>a</i>]pyrimidine analogues from easily accessible starting materials in an ecologically friendly and efficient approach. This method is notably helpful for producing physiologically relevant compounds containing the imidazopyrimidine unit, which serves as a versatile building block for the synthesis of <i>N</i>-fused heterocycles and is devoid of metals, solvents, additives, and catalysts. Additionally, utilizing ultrasound in an open-air environment, a range of polyfluoro-ynones were successfully reacted with 2-aminobenzimidazole, generating a diverse array of polyfluoroimidazo[1,2-<i>a</i>]pyrimidine derivatives. Furthermore, by employing an integrated flow system approach, we were able to synthesize polyfluoro-substituted benzo[4,5]imidazo[1,2-<i>a</i>]pyrimidine derivatives from alkynes with a much shorter reaction time. Gram-scale synthesis proved this method's scalability and highlighted its potential for synthetic and industrial applications. The straightforward nature of the process, broad compatibility with various functional groups, and substantial sustainability advantages collectively underscore its significance.