3-Selective Halogenation of Pyridines via Zincke Imine Intermediates

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.