AUTOMATION & CHEMOMETRICS ENABLE NOVEL TRIFLUOROMETHYL BENZOXABOROLE SYNTHESIS

Over recent decades, boron has emerged as a prominent element in medicinal chemistry, with benzoxaboroles standing out as one of the most significant boron-containing scaffolds. In this talk, I will discuss the synthesis of a novel class of benzoxaboroles — namely 3-trifluoromethyl-benzoxaboroles — whose preparation was achieved through a chemometric approach. Among the parameters optimised using chemometric tools such as D-Opt and full factorial design, the most notable improvement was the increase in reaction temperature from −78 °C to ambient, highlighting this methodology as a valuable tool for promoting sustainability in chemical synthesis. A broad range of 3-trifluoromethyl-benzoxaboroles was successfully synthesised, demonstrating excellent functional-group tolerance toward alkyl, halogen, electron-withdrawing, and electron-donating substituents, including ortho-substituted derivatives. This library also encompasses five- and six-membered heterocyclic oxaboroles, representing an unexplored chemical space for this class of boron heterocycles. Moreover, a series of post-synthetic functionalisation strategies for these new benzoxaboroles was developed, including electrochemical nickel-catalyzed cross-coupling reactions with redox-active esters — a radical pathway not previously explored for benzoxaborole modification. Finally, the synthesis was adapted to a robotic platform, enabling the fully automated preparation of 3-trifluoromethyl-benzoxaboroles without human intervention.