Carbon-carbon bond formation reactions are some of the most important processes in chemistry, which provide key steps in the building of more complex molecules from simple precursors. The palladium-catalyzed cross-coupling reaction represents one of the most straightforward method for carbon-carbon bond formation. Among palladium-catalyzed cross-coupling processes, the Suzuki reaction of aryl and vinyl halides or triflates with organoboron compounds provides a powerful and general methodology, which is emerging as a favorite. A brief introduction is given in Chapter 1 with an emphasis on the background information closely related to the topics of this thesis....[ Read more ]

Carbon-carbon bond formation reactions are some of the most important processes in chemistry, which provide key steps in the building of more complex molecules from simple precursors. The palladium-catalyzed cross-coupling reaction represents one of the most straightforward method for carbon-carbon bond formation. Among palladium-catalyzed cross-coupling processes, the Suzuki reaction of aryl and vinyl halides or triflates with organoboron compounds provides a powerful and general methodology, which is emerging as a favorite. A brief introduction is given in Chapter 1 with an emphasis on the background information closely related to the topics of this thesis.

In recent years, use of transition metal complexes of electron-rich and steric bulk phosphines in the palladium-catalyzed Suzuki cross-coupling reaction has led to important advances, and it becomes a topic of ever growing interest. We present in Chapter 2 a family of air-stable P,O-ligands (Aphos) for palladium-catalyzed Suzuki coupling reaction of unactivated aryl chlorides. The simple and high-yielding synthesis method of this type of ligands is mentioned. It is followed by the details of employing the Aphos ligands in Suzuki coupling of diverse aryl chlorides and aryl boronic acids, including details on optimization of the reaction conditions, scope, and limitation.

Axially chiral biaryls are common structural motifs in natural products and are the core for many of the most effective chiral ligands. Recently, asymmetric Suzuki cross-coupling appears to be one of the most powerful method for chiral biaryl synthesis. However, only two types of chiral ligands have been used in catalytic enantioselective Suzuki couplings: the binaphthyl and the ferrocenyl ligands. Most of them were not efficient in inducing high enantioselectivity in biaryl synthesis. In Chapter 3, we introduce the atropisomeric 1-naphthamide-derived P,O-ligands (A²phos). The synthetic procedure, stereochemistry determination, and applications of A²phos in asymmetric Suzuki coupling of aryl bromides with aryl boronic acids are detailed, leading to up to 91% ee in formation of unsymmetrical biaryls.

Chapter 4 focuses on development of a microwave-based high-throughput protocol for optimization of Aphos ligands with improved catalytic efficiency. A combinatorial approach featured with a novel self-assisted molecular evolution (SAME) concept for generation of molecular diversity is realized in the synthesis of a 20-member ligand library. This effort leads to discovery of an excellent X-Cy-Aphos capable of promoting Suzuki cross-coupling of unactivated aryl chlorides at room temperature. Although the results are still very preliminary, the SAME strategy should find potential application in area where molecular diversity is needed for exploration of chemical space.

Overall, this thesis presents a compilation of our original and attractive research efforts on palladium-catalyzed Suzuki coupling reactions and its asymmetric version with an emphasis on the powerful ligands discovery.