Flow Synthesis of Fluorinated α-Amino Acids

Fluorinated α‐amino acids are versatile compounds that are used for many purposes in medicinal and biochemistry. However, their synthesis remains a significant hurdle, often requiring multiple steps, multiple protecting groups, and/or the use of highly toxic reagents. These challenges have limited the application of fluorinated α‐amino acids. A convenient, protecting‐group‐free and semi‐continuous process for the synthesis of racemic fluorinated α‐amino acids from fluorinated amines is described. Following a singlet‐oxygen‐driven photooxidative cyanation, an acid‐mediated hydrolysis of the intermediate α‐amino nitrile yields the desired α‐amino acid. Aliphatic, benzylic, and homobenzylic residues with different fluorination degrees are tolerated, providing good overall yields (50–67 %). This semi‐continuous process is particularly advantageous for an aliphatic amine, the intermediate α‐amino nitrile of which decomposes upon isolation. An efficient, semi‐continuous, and protecting‐group‐free method for the synthesis of fluorinated α‐amino acids from the corresponding amines has been developed. A low temperature photooxidative cyanation of benzylic and aliphatic amines provided α‐amino nitriles with varying fluorination patterns. These unstable intermediates were trapped with an acid‐mediated hydrolysis with good overall yields.