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

作者：Qi Zhang, Xue‐Song Yin, Kai Chen, Shuo‐Qing Zhang, Bing‐Feng Shi · 发表于：Journal of the American Chemical Society · 年份：2015 · DOI：10.1021/jacs.5b03989 · 被引用次数：212 · 研究领域：Fluorine in Organic Chemistry、Catalytic C–H Functionalization Methods、Radical Photochemical Reactions

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.