Development of a More Sustainable Appel Reaction

Herein,
we report a green, chromatography-free Appel chlorination
and bromination in both catalytic and stoichiometric form. Improved
sustainability was achieved via the effective replacement of chlorinated
solvents with dimethyl carbonate and the use of triphenylphosphine
oxide (PPh3O) as a recyclable organocatalyst. The substrate
scope of this halogenated solvent-free reaction was shown to be analogous
to a contemporary methodology, and removal and recovery of PPh3O from the desired products were effectively demonstrated.
Investigations into the catalytic cycle were conducted, and REACT-IR
was demonstrated to be an effective method of reaction monitoring
in situ. Optimized methodology was applied to the synthesis of 1-bromo-4-(1-bromoethyl)­benzene,
a key building block employed during the discovery of a GSK fatty
acid synthase inhibitor.