The impact of axial chirality on the biological activity of small molecule drug compounds has been demonstrated in the numerous FDA-approved drugs containing biaryl systems. Such compounds exhibit axial chirality as a result of the restricted rotation imposed by substitution around the central C–C bond. As an analogue of biaryl systems, the N-Aryl 2-pyridone motif has emerged as a privileged scaffold in medicinal chemistry, with particular applications in immunology and oncology, reflected in the recent increase in FDA approved drugs bearing this motif. In N-aryl 2-pyridones, the axial chirality derived from restricted rotation around the C–N axis provides the opportunity to unlock new modes of target binding, and thus this motif has become of great interest in drug-candidate design. Current methods for the synthesis of hindered N-aryl 2-pyridones typically rely on multistep syntheses of acyclic precursors, followed by an amide bond-forming cyclisation to form the pyridone heterocycle. Although methods for the direct arylation of 2-pyridones do exist, these are plagued with selectivity issues arising from competitive O-arylation. Even in simple unsubstituted systems, no general methods exist that allow selective N-arylation of 6-substituted 2-pyridones from feedstock chemicals. The development of a method enabling the direct, selective N-arylation of 6-substituted 2-pyridones would streamline the synthesis of these medicinally important scaffolds, enabling more efficient exploration of this exciting area of pharmaceutically-relevant chemical space. In this work, we designed a mechanistically distinct photocatalytic activation mode that enables the selective cross-coupling of aryl iodides and substituted 2-pyridones. A key design element in the new process was the photocatalytic generation of a previously underexplored N-centred pyridonyl radical intermediate, which is believed to impart previously inaccessible exclusive N-selectivity on the reaction. Integral to the realisation of this process was the development of a high-throughput reaction discovery platform which dramatically accelerated the discovery and optimisation of the new process. We believe that this transformation will be of great value to medicinal chemists, while also addressing a significant gap in the C-N cross coupling literature.

Yusra Abdelhamid

University of Cambridge

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