The Superbase Approach to Flurbiprofen: An Exercise in Optionally Site-Selective Metalation

Abstract

The structure of the antiinflammatory drug flurbiprofen [2-(2-fluoro-4-biphenylyl)propionic acid] presents a simple but challenging target to practice regiocontrolled assembly of molecular subunits through optionally site-controlled metalation. The short and efficacious sequence shown leads to the final product: a four-step, one-pot conversion of 3-fluorotoluene into 2-fluoro-4-methylbiphenyl (79%), consecutive deprotonation and carboxylation (84%) of the benzylic methyl group, and, finally, α-deprotonation again followed this time by methylation (92%).