Hydrogen Bond Directed Photocatalytic Hydrodefluorination: Overcoming Electronic Control

The photocatalytic C–F functionalization of highly fluorinated
arenes is a powerful method for accessing functionalized multifluorinated
arenes. The decisive step in the determining regioselectivity in fluorine
functionalization is fluoride fragmentation from the radical anion
of the multifluorinated arene. To date, the availability of regioisomers
has been dictated by the innate electronics of the fluorinated arene,
limiting the synthetic utility of the chemistry. This study investigates
the remarkable ability of a strategically located hydrogen bond to
transcend the normal regioselectivity of the C–F functionalization
event. A significant rate acceleration is additionally observed for
hydrodefluorination of fluorines that can undergo intramolecular hydrogen
bonds that form 5–8-membered cycles with moderately acidic
N–H’s. The hydrogen bond is expected to facilitate the
fragmentation not only by bending the C–F bond of the radical
anion out of planarity but also by increasing the exothermicity of
the fluoride extrusion step through protonation of the naked fluoride.
Finally, the synthetic utility of the method is demonstrated in an
expedited synthesis of the trifluorinated α-phenyl acetic acid
derivative required for the commercial synthesis of Januvia, an antidiabetic
drug. This represents the first synthesis of a commercially important
multifluorinated arene via a defluorination strategy and is significantly
shorter than the current strategy.