Bidentate N-heterocyclic carbenes as efficient ligands for Ullmann-type couplings

Abstract

Diaryl ethers are important motifs present in pharmaceuticals and natural products. However, well established methods for their preparation often make use of expensive and toxic transition metal catalysts or suffer from poor catalytic efficiency and substrate scope; often requiring the use of harsh and environmentally impactful reaction conditions. This thesis details the development of a new bidentate N-heterocyclic carbene (NHC) ligand intended to address these significant issues in copper-catalysed Ullmann-type phenol arylation. To begin with, Section 2 describes the synthesis of a library of NHC ligands bearing a second, heteroatomic coordinating site. The ligand structure-activity-relationship is investigated and the reaction conditions optimised, resulting in a highly efficient system using low catalyst loadings (0.1 0.5 mol %) in greatly reduced solvent volume and using only 1.1 equiv of Cs2CO3 as base. This system is then applied to challenging substrates in Section 2.7 including heteroaromatic examples, those bearing ortho-substituents, electron poor phenols and electron rich aryl bromides. Following this, Section 3 details the evaluation of the functional group tolerance of the newly developed system, which was carried out through a Glorius robustness screen. The majority of additives were well tolerated under the reaction conditions with minimal impact upon diaryl ether yield. Section 3 culminates with the parallel array synthesis of functionalised diaryl ethers, possessing desirable drug- and lead-like physical properties. The preparation of well-defined copper-NHC complexes is then discussed in Section 4. A series of key mono- and bis-NHC copper complexes featuring the newly developed ligands were isolated and characterised, with the coordination of the bidentate ligand revealed in their crystal structures. These copper catalysts were found to perform to the same level as the in situ generated, implying that they bear a close resemblance to the active species. Efforts were also made to isolate a copper(I)-phenolate complex. Finally, details of kinetic studies are discussed in Section 5, which revealed the important role of the bidentate ligand in preventing catalyst deactivation, as well as a first order rate dependence in the concentration of catalyst and phenol. The order in base was found to be negligible and no effect on reaction rate was observed by mass transfer.