Ligand-enabled advances in Ni-catalyzed cross-coupling

Abstract

Due to their abundance in bioactive molecules, the construction of C(sp2)-X bonds (X = C, N, O) using cheap and abundant aryl electrophiles is centrally important in synthetic organic chemistry. Homogeneous catalysis has enabled these transformations to be carried out at relatively mild temperatures and pressures, using relatively mild reagents, allowing broad adoption throughout industry. However, despite the impact of Pd-catalyzed cross-couplings on industrial small molecule synthesis, the development of more sustainable technologies, including those that rely on more Earth-abundant metals such as Cu and Ni, are of immense importance. This thesis describes my contributions to Ni-catalyzed cross-coupling, in pursuit of more sustainable methods relevant to industry. The first of these is the synthesis of a simplified variant of the chiral bisphosphine ligand JosiPhos CyPF-Cy that enables similar reactivity in the cross-coupling of ammonia and primary amines with (hetero)aryl chlorides, carbamates, and sulfamates without the need for a chiral ligand. Next, I will present the Ni-catalyzed C-O cross-coupling of phenols with (hetero)aryl chlorides, outlining how PAd2-DalPhos and PhPAd-DalPhos ligands enable the synthesis of pyridyl-O-aryl motifs, which are relatively under-reported in the context of Ni-catalyzed diaryl ether synthesis. Finally, I will outline my work on C2-H arylation of 1,3-oxazole and 1,3-thiazole derivatives, which seeks to address limitations in the few existing Ni-catalyzed methods for these couplings by using Ni(II) precatalysts incorporating CyPAd-DalPhos and PhPAd-DalPhos. The practicality of this method is demonstrated through the derivatization of an API electrophile, and gram-scale regioselective arylation of thiazole. Optimized methods for each of these transformations also incorporate the use of soluble organic bases alongside a sodium trifluoroacetate additive. These so-called “dual base” systems enable the end user to avoid the use of strong inorganic bases which often introduce issues related to solubility and functional group tolerance.