Direct, regioselective functionalization of the C-H bond in pyridines is highly sought after due to pyridine’s prevalence in many FDA-approved drugs. Here, we describe two strategies to functionalize pyridines, controlled by the pKa of the conjugate acid formed in the reaction. Both methods rely on pyridine activation and dearomatization to make two distinct products. The first is through a “ring-opening” process that changes the electronics of the pyridine to form a push-pull pi-system. The second is by creating a “ring-closed” intermediate after the addition of a nucleophile. Both methodologies lead to the formation of valuable bonds that are important for drug discovery.

Site-Selective Pyridine Functionalization via Nucleophilic Additions to Activated Pyridiniums

ACS Spring 2022

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