Ylide-Substituted Phosphines in Palladium-Catalyzed Coupling Reactions

Abstract

Palladium-catalyzed coupling reactions have become an indispensable tool for the formation of complex organic molecules. Many advances have benefited from the development of new, sophisticated ligands, particularly electron-rich organophosphines. This review provides an overview of the development of these phosphines for application in palladium-catalyzed cross-couplings. It focuses on recently reported ligands with donor capacities beyond tri(tert-butyl)phosphine, in particular the highly electron-rich, ylide-substituted phosphines developed in our group.

Introduction

Palladium-catalyzed coupling reactions have developed into one of the most important methodologies for the construction of carbon–carbon and carbon–heteroatom bonds. Owing to the reliability of many coupling protocols, their broad substrate scope, mildness, and efficiency, this methodology has become indispensable for the formation of complex molecules such as pharmaceuticals, agrochemicals, and organic materials. Accordingly, the pioneering work done in this area by Richard F. Heck, Akira Suzuki, and Ei-ichi Negishi was recognized with the awarding of the Nobel Prize to those three in 2010.¹ Since then, the field has seen continuous advances many of which have been connected with the development of new, more effective catalysts. Although many transition metals have been shown to promote coupling reactions, palladium remains in general the most effective and hence most applied metal in this type of chemistry.

Organophosphines are the dominant class of ligands in this area. The tuning of their electronic and steric properties to accelerate the rate-limiting step within the catalytic cycle has enabled many advances. Early work has focused on the use of simple arylphosphines, with PPh₃ remaining one of the most applied phosphine ligands for the coupling of aryl iodides and bromides owing to its cost-effectiveness. Further Ylide-Substituted Phosphines in Palladium-Catalyzed Coupling Reactions Daniel Knyszek and Viktoria H. Gessner^* improvements were achieved by the use of diphosphines; followed by electron-rich, bulky alkylphosphines, which currently dominate advanced applications such as the coupling of aryl chlorides and triflates.² The search for strongly electron- donating monophosphines started with the use of tri(tert- butyl)phosphine, P(t-Bu)₃, introduced by Fu in 1998.³ Since then, various types of alkylphosphines have been reported and are nowadays commercially available. In this review, we focus on phosphines exceeding the donor strength of P(t-Bu)₃, concentrating on our previously reported ylide-functionalized phosphines, which we discuss in the context of the ongoing development of electron-rich ligands and their impact on coupling chemistry.

Conclusions

Although ylide-substituted phosphines (YPhos) only found applications in homogeneous catalysis for the first time in 2018, this class of ligands has already demonstrated its impressive capabilities in homogeneous catalysis, particularly in palladium-catalyzed coupling reactions. Their increased donor capacity compared to traditional trialkylphosphines enables their palladium complexes to easily activate the otherwise less reactive aryl chlorides, making these substrates accessible for new applications at milder reaction conditions. The modular structure of YPhos ligands, in combination with their straightforward preparation, allows the fine-tuning of their properties and hence their easy optimization for different applications. This flexibility of the YPhos ligands is important for future catalyst design, in particular computationally derived structure predictions based on structure–activity relationships.