ja5b03989_si_009.cif (33.06 kB)
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
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posted on 2015-07-01, 00:00 authored by Qi Zhang, Xue-Song Yin, Kai Chen, Shuo-Qing Zhang, Bing-Feng ShiThe 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.