Fluorinated heterocycles are prevalent in pharmaceutical and agrochemical compounds. However, reactions that incorporate fluorine into heteroarenes are limited in scope and often require hazardous reagents. We present a broadly applicable method for the site-selective fluorination of a single C-H bond in pyridines and diazines using inexpensive ($1/mmol) and commercially available AgF2. These reactions occur at ambient temperature within one hour with exclusive selectivity for fluorination adjacent to nitrogen. The mild conditions allow access to fluorinated derivatives of numerous medicinally important compounds. Our mechanistic studies demonstrate that the pathway of a classic pyridine amination can be adapted for selective fluorination of nitrogen heterocycles.In addition to being useful final compounds, the fluorinated heterocycles prepared in these reactions can be further elaborated through nucleophilic aromatic substitution (SNAr) with a range of O, N, S, and C-based nucleophiles. We demonstrate that this strategy of tandem C-H fluorination and SNAr chemistry allows rapid access to several medicinal compounds along with a broad range of otherwise difficult to prepare derivatives.

Selective C-H fluorination of pyridines and diazines: Development and applications to late-stage functionalization

248th National Meeting (2014)

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