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Selective C-H Fluorination of Pyridines and Diazines Inspired by a Classic Amination Reaction

Science  22 Nov 2013:
Vol. 342, Issue 6161, pp. 956-960
DOI: 10.1126/science.1243759

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Fluorinating Pyridine

Appending fluorine substituents to carbon centers is commonly used to tune small-molecule properties in pharmaceutical and agrochemical research. However, fluorinations often require the use of corrosive, hazardous reagents. Fier and Hartwig (p. 956) present an unusually mild and convenient protocol for fluorinating carbon sites adjacent to nitrogen in pyridines and related nitrogen-bearing arenes. The reaction entails treatment with silver difluoride and proceeds rapidly at room temperature.

Abstract

Fluorinated heterocycles are prevalent in pharmaceuticals, agrochemicals, and materials. However, reactions that incorporate fluorine into heteroarenes are limited in scope and can be hazardous. We present a broadly applicable and safe method for the site-selective fluorination of a single carbon-hydrogen bond in pyridines and diazines using commercially available silver(II) fluoride. The reactions occur at ambient temperature within 1 hour with exclusive selectivity for fluorination adjacent to nitrogen. The mild conditions allow access to fluorinated derivatives of medicinally important compounds, as well as a range of 2-substituted pyridines prepared by subsequent nucleophilic displacement of fluoride. Mechanistic studies demonstrate that the pathway of a classic pyridine amination can be adapted for selective fluorination of a broad range of nitrogen heterocycles.

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