Photochemical selective difluoroalkylation reactions of bicyclobutanes: direct sustainable pathways to functionalized bioisosteres for drug discovery

Abstract

In the realm of organic and green chemistry, the functionalization of cyclobutanes presents a significant challenge, given their unique structural properties and biological relevance. Particularly, the introduction of difluoromethyl groups into cyclobutane frameworks is a burgeoning area of interest due to their potential in drug design and synthesis. However, the construction of difluoromethyl cyclobutanes heavily relies on the environmentally burdensome fluorination of cyclobutyl ketones. Methods to efficiently and directly introduce difluoromethyl groups into cyclobutanes remain underexplored. This study introduces a novel photochemical protocol for the selective difluoromethylation or bromo difluoromethylation of bicyclobutanes, leveraging green solvent-controlled reactions. Remarkably, this method exhibits the merits of both green chemistry and organic chemistry such as renewable visible light as reaction power, high atom economy and fully controlled chemo-selectivity. This work also reveals the mechanism behind the remarkable selectivity achieved. Emphasizing the importance of difluoromethyl cyclobutane scaffolds as bioisosteres, this research not only broadens the chemical space in organic synthesis but also offers new avenues for pharmaceutical discovery. The findings demonstrate the robustness and versatility of the method, including its applicability to drug modifications, addressing a crucial gap in the green synthesis of complex medicinal molecules.