Energy-Transfer Catalysis Enables the Birch-Type Reduction of 2-Pyridones.

Hartmann P; Liljenberg S; Domack J; Hölter N; Daniliuc C; Glorius F

Abstract

Partially saturated heteroarenes are key intermediates in drug development, as their increased C(sp3) character and inherent synthetic versatility enable the rapid generation of improved lead structures. Despite their value, direct access from their aromatic precursors under Birch conditions remains limited due to safety, as well as chemoselectivity challenges. In this context, energy-transfer (EnT)-enabled Birch-type reductions have emerged as a powerful strategy for (chemo)selective product formation. However, it has been largely confined to bicyclic (hetero)arenes, while their more prevalent monocyclic counterparts remain vastly underexplored. Herein, we describe the triplet sensitized, partial saturation of 2-pyridones and their derivatives, which are known as privileged scaffolds in drug discovery. Our methodology shows exceptional regioselectivity for the Birch-type product and tolerates a vast number of functional groups, bypassing conventional highly reducing reaction conditions. The reaction mechanism was investigated experimentally and computationally, providing strong evidence for the proposed EnT-HAT reaction pathway and rationalizing the observed regioselectivity. Lastly, the versatile and underexplored product motifs could be applied in downstream modifications to expand the drug-like C(sp3)-rich chemical space.