Stereoselective Synthesis of Chiral β‑Fluoro α‑Amino Acids via Pd(II)-Catalyzed Fluorination of Unactivated Methylene C(sp³)–H Bonds: Scope and Mechanistic Studies

The synthesis of fluorinated complex molecules via direct C­(sp3)–H fluorination is attractive yet remains challenging. Here we describe the Pd­(II)-catalyzed fluorination of unactivated methylene C­(sp3)–H bonds by an inner-sphere mechanism. This method allows the site- and diastereoselective fluorination of β-methylene C­(sp3)–H bonds of α-amino acid derivatives. A range of substrates containing both aliphatic and benzylic C­(sp3)–H bonds were compatible with this protocol, leading to an array of β-fluorinated α-amino acids. Stoichiometric fluorination of an isolated palladacycle intermediate takes place rapidly under very mild reaction conditions (room temperature, 5–10 min). Data from preliminary mechanistic studies are consistent with direct C–F reductive elimination from a high-valent intermediate.