Organic Chemistry

3-Selective Halogenation of Pyridines via Zincke Imine Intermediates

Authors

Abstract

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. Yet, despite more than a century of synthetic endeavors, there are no broadly applicable 3-selective halogenation processes that function directly from pyridine C–H precursors. We have developed a ring-opening, halogenation, ring-closing sequence that temporarily transforms pyridines into a reactive series of alkenes. These Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the selectivity-determining step changes based on the halogen electrophile. Using this method, we formed a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

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Updated SI

Content

Thumbnail image of Zincke Halogenation-XIX-ChemRxiv.pdf

Supplementary material

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Supporting Information
Supporting Information
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Thermochemical and Structural Data
Thermochemical and Structural Data