Development of phosphine ligands for efficient and chemoselective palladium-catalysed cross-coupling reactions

Abstract

Design and synthesis of novel phosphine ligands is one of the most enduring and fascinating research areas for chemists. These new designs aim to improve reactions with harsh conditions or achieve challenging goals in transition metal-catalysed reactions. This thesis focuses on the utility of newly synthesised phosphine ligands in Pd-catalysed cross-coupling reactions. Following a brief introduction to the development of phosphine ligands utilised in palladium catalysis, Chapter 2 discusses the synthesis of sterically hindered biaryls using an indole-amide-based phosphine ligand in Pd-catalysed Suzuki–Miyaura cross-coupling reactions. This method achieves excellent yields in short reaction times, such as 10 minutes, and with extremely low palladium catalyst loadings down to 50 ppm. As these target compounds serve as the fundamental framework for materials science and pharmaceutical agents, this more efficient, milder, and more diverse synthetic route remains alluring. From Chapter 3 onwards, the thesis explores the unconventional and specific chemoselectivity exhibited by a series of C2-alkylated indole-based phosphine ligands in Pd-catalysed borylation. Polyhalogenated aryl triflates, which have multiple reactive sites, were traditionally believed to follow the reactivity order of C–Br > C–OTf > C–Cl. However, this chapter reports a Pd-catalysed chemoselective borylation reaction with a reactivity order of C–Cl > C–OTf. SelectPhos achieves high reactivity and chemoselectivity through a C–H–Pd interaction involving the methine hydrogen of the C2-alkyl group. This interaction may help stabilise the palladium centre and facilitate the activation of the C–Cl bond. Additionally, the catalyst can perform a one-pot two-step sequence of chemoselective borylation followed by intermolecular Suzuki–Miyaura coupling to synthesise asymmetric biaryls containing triflate moieties, paving the way for the synthesis of complicated terphenyls. The properties of these ligands form the basis for Chapter 4, where 2-alkylated indole-based phosphine ligands are applied to achieve a reactivity order of C–Br > C–Cl > C–OTf in Suzuki–Miyaura cross-coupling reactions with polyhalogenated aryl triflates. Various bromo(hetero)aryl triflates were successfully coupled with (hetero)arylboronic acids, achieving excellent reactivity and chemoselectivity. This catalyst is active at a remarkably low palladium loading of 0.02 mol%. This system demonstrates a sequential dual functionalisation of bromochloroaryl triflates, laying the groundwork for synthesising triphenyl and its derivatives.