Abstract
Palladium-catalysed cross-coupling reactions have revolutionised the way in which molecules are constructed. However, there is still a growing need to design and develop effective and easily tunable ligands. It is well-established that bulky electron-rich phosphine ligands facilitate the catalytic cycle’s oxidative addition and reductive elimination steps. For example, P(alkyl)3 (alkyl = Cy, tBu and Ad) and dialkylbiaryl phosphines have significantly impacted the development of various Pd-catalysed cross-coupling reactions. Thus, in this research study, we designed P-bridged phosphines and investigated their stereoelectronic properties, and evaluated their potential as phosphine ligands in Pd-catalysed α-arylation reactions.
The ligand design of the proposed ligands (Chapter 2) is based on combining the benefits of the easily tunable, robust biphenyl functionality and the inherently rigid 9-phosphabicyclononane (phob) and phosphatrioxa-adamantane (Cg) frameworks. The ligands were successfully synthesised in moderate to good yields (59% – 72%). Furthermore, oxidation studies revealed the ligands to be relatively air and moisture-stable at ambient conditions. To understand their steric and electronic properties, classical experimental and theoretical parameterisation techniques were investigated. These studies demostrated the biphenyl phob ligands L1 and L2 to be more electron-rich and less bulky than the Cg-based ligand L3.
We first investigated the catalytic potential of the phobane ligands L1 and L2, as well as their isomeric mixture (L1:L2 – 1:7) in Pd-catalysed α-arylation of aryl bromides and chlorides (Chapter 3). A variety of aryl halides were successfully coupled at 130 °C, with L1 being marginally more effective than L2. On the other hand, Pd-catalysed α-arylation reactions featuring the strongly electron-deficient and bulkier biphenyl Cg ligand L3 were conducted efficiently at relatively milder reaction conditions (40 – 80 °C, Chapter 4). This observation is attributed to the optimal steric bulk of L3, suggesting that the ligand’s electronic parameter contributed less to the catalytic activity.
Chapter 5 highlighted our attempts towards Pd-catalysed α-arylation of aldehyde and nitrile nucleophiles, as well as Buchwald-Hartwig amination using biphenyl Cg ligand L3. The former reactions proved challenging under the previously optimised α-arylation reaction conditions and will further need optimisation. However, Buchwald-Hartwig amination reactions were successfully optimised using activated aryl bromide and further demonstrated with one aryl chloride at 60 °C.