Light-Mediated Dual Catalysis for C–N Bond Formation

Abstract

The advent of dual catalysis for organic synthesis, involving the implementation of two catalytic species in a single reaction process, has allowed new streamlined and efficient synthetic methods to be developed. This thesis describes efforts towards the development of novel transformations for radical C–N bond formation mediated by photoredox dual catalytic systems. First, investigation into the development of a new transformation to generate b-phenylethylamine scaffolds, a valuable motif that is found in a range of pharmaceutically active compounds, is presented. 1,2 This was achieved through the design of a visible- light mediated dual-catalytic platform that enabled multicomponent coupling of alkenes, aryl electrophiles and a nitrogen nucleophile to form b-aryl azidoalkanes.3 Mechanistic studies revealed the role of the azide anion both as a nitrogen source and in mediating key catalytic cycle turnover in this net redox-neutral process. The broad scope showcased enabled the single-step synthesis of a variety of functionally diverse b-phenylethylamines. Subsequent development of an asymmetric variant of the reaction was also investigated using a chiral group transfer catalyst to enable enantioselective azide addition. Secondly, the development of a dual catalytic strategy towards the synthesis of highly substituted and conformationally stable N-aryl-2-pyridones is described. This motif has emerged as a privileged scaffold in medicinal chemistry with applications in immunology and oncology, evidenced by the recent FDA approval of KRAS inhibitor sotorasib.4 This work describes the design of a mechanistically distinct photocatalytic activation mode that enabled the selective cross-coupling of aryl iodides and 6-substituted 2-pyridones. Mechanistic investigations revealed the participation of a key N-centred pyridone radical intermediate, which allowed complete N-selectivity to be achieved in the cross-coupling route to hindered aza-biaryl structures. Integral to the realisation of this process was the development of a high-throughput (HT) reaction discovery platform which dramatically accelerated the discovery and optimisation of the new process.