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The synthesis of fluorinated complex molecules via direct C(sp(3))-H fluorination is attractive yet remains challenging. Here we describe the Pd(II)-catalyzed fluorination of unactivated methylene C(sp(3))-H bonds by an inner-sphere mechanism. This method allows the site- and diastereoselective fluorination of β-methylene C(sp(3))-H bonds of α-amino acid derivatives. A range of substrates containing both aliphatic and benzylic C(sp(3))-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.

A Pd(II)-catalyzed arylation of methylene C(sp(3))-H bonds in aliphatic amides directed by our newly developed PIP directing group with aryl iodides/bromides has been achieved. Arylation occurs efficiently with a broad range of aryl halides and amides.