Pd-Catalyzed C(sp²)-C(sp³) Suzuki Coupling and Synthesis of Lumacaftor Using Designed Monophosphine Ligands

Novel monophosphine ligands L1 and L2 with a C-P ring were designed and synthesized for the efficient Pd-catalyzed C(sp²)-C(sp³) Suzuki coupling. With 0.5 mol % Pd₂dba₃ and 2 mol % L1, aryl halides coupled with alkylboronic acids to give the products in up to 99% yield. The aryl thianthrene salt was further applied for late-stage methylation in 97% yield. The active pharmaceutical ingredient lumacaftor was synthesized by aryl-alkyl and aryl-aryl Suzuki coupling reactions using L1 and L2.