Molecular Sculpting: A Multipurpose Tool for Expedited Access to Various Fluorinated Arenes via Photocatalytic Hydrodefluorination of Benzoates

Starting with highly fluorinated benzoates, we develop
the directed
photocatalytic hydrodefluorination (HDF) of fluorinated aryl benzoates
and demonstrate its synergistic use with other HDF strategies, along
with C–H arylation, decarboxylative coupling, and decarboxylative
protonation, to access most fluorination patterns found in benzoate
derivatives and by extension benzene derivatives via a molecular sculpting
approach. Mild reaction conditions and excellent regioselectivity
make the approach ideal for synthesis. This approach provides access
to 16 benzoate derivatives with different fluorination patterns from
just a couple of highly fluorinated, commercially available benzoic
acids. We synthesize key intermediates or the active pharmaceutical
ingredient for sitagliptin, diflunisal, and other pharmaceutically
important molecules. Importantly, we provide key insights into relative
rates of defluorination and strategies to alter these rates. We provide
demonstrations of the synergistic use of HDF and related technologies
to rapidly enhance the synthetic complexity of these simple commercially
available perfluoroarenes to form complex partially fluorinated molecules.