Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene

Fluoroalkyl arenes are essential in pharmaceutical development, with groups like CF3, CF2H, CH2CF3, and cyclopropyl-CF3 significantly enhancing medicinal properties. However, current methodologies that rely on metal-catalyzed cross-coupling reactions face challenges such as reductive elimination and limited reagent availability. This study introduces an alternative approach, leveraging Si/F non-covalent interactions for the first time in transition metal catalysis. This enables distal C−H functionalization of di- and tri-fluoroalkyl arenes using commercially available fluoroalkyl reagents and coupling partners, achieving meta-selectivity. The process facilitates the efficient synthesis of pharmacologically relevant compounds, including Cinacalcet, TrxR1, and the herbicide tetflupyrolimet, advancing sustainable and economical drug discovery. By employing a silicon-containing directing ligand, the approach ensures site-selective functionalization, marking a significant step toward green and efficient synthetic strategies.