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.