Photocatalytic Diverse Synthesis of Transformable SF5-Scaffolds Utilizing SF6

The efficient incorporation of fluorinated motifs into drug candidates remains a key goal in pharmaceutical lead optimization. Among these, pentafluorosulfanyl (SF5) group, regarded as “super-trifluoromethyl”, stands out due to its unique octahedral geometry, high electronegativity, and exceptional lipophilicity. Despite growing interest in SF5-containing pharmacophores, current strategies mainly focus on aromatic drugs, with few approaches available for introducing SF5 groups into more diverse structural frameworks. In this context, the potent greenhouse gas sulfur hexafluoride (SF6), a non-toxic, inexpensive, and stable alternative to the widely used but hazardous SF5Cl, offers an attractive source of SF5 groups. However, its use as a reagent for pentafluorosulfanylation reactions remains rarely explored. Herein, we report a photocatalytic strategy for directly synthesizing diverse SF5-containing scaffolds, including ketones, acetals and bicyclo1.1.1pentane derivatives, using SF6 as pentafluorosulfanylation reagent. The usefulness of this method is demonstrated through derivatization studies, particularly the production of synthetically valuable α-SF₅-substituted acetaldehydes. Mechanistic studies supported by DFT calculations reveal that the transformation occurs via a single electron reduction of SF6, providing insight into its activation pathway. This photocatalytic approach operates under mild conditions with broad functional group compatibility, offering a platform for the construction of SF5-functionalized scaffolds and expanding the toolbox for fluorinated drug discovery.