Switchable 1,2-Rearrangement Enables Expedient Synthesis of Structurally Diverse Fluorine-Containing Scaffolds

Skeletal rearrangement that changes the connectivity of the molecule via cleavage and reorganization of carbon-carbon bonds is a fundamental and powerful strategy in complex molecular assembly. Because of the lack of effective methods to control the migratory tendency of different groups, achieving switchable selectivity in skeletal rearrangement has been a long-standing quest. Metal-based dyotropic rearrangement provides a unique opportunity to address this challenge. However, switchable dyotropic rearrangement remains unexplored. Herein, we show that such a problem could be solved by modifying the ligands on the metal catalyst and changing the oxidation states of the metal to control the migratory aptitude of different groups, thereby providing a ligand-controlled, switchable skeletal rearrangement strategy. Experimental and density functional theory calculation studies prove this rational design. The rearrangement occurs only when the nickel(II) intermediate is reduced to a more nucleophilic nickel(I) species, and the sterically hindered iPrPDI ligand facilitates 1,2-aryl/Ni dyotropic rearrangement, while the terpyridine ligand promotes 1,2-acyl/Ni dyotropic rearrangement. This method allows siteselective activation and reorganization of C-C bonds and has been applied for the divergent synthesis of four medicinally relevant fluorine-containing scaffolds from the same starting material.

Automated summary

Switchable selectivity in skeletal rearrangement can be achieved by controlling the migratory aptitude of different groups. Modifying the ligands on the metal catalyst and changing the oxidation states of the metal allow control over the migratory ability. This method enables site-selective activation and reorganization of C-C bonds and has been used for the synthesis of fluorine-containing scaffolds with medicinal relevance.