C5-Halogenation of Pyridines via Zincke Iminium Intermediates

Recently, several methods for pyridine halogenation have emerged, but a robust 5-selective platform has yet to be developed. Here, we report a ring-opening, halogenation, and ring-closing sequence for C5-pyridine iodination and bromination. The process exploits Zincke iminium salts that undergo C5-selective halogenation with N-halosuccinimides, thereby switching the selectivity from the C3-position in our previous work with NTf-Zincke imines. The reaction does not require blocking substituents at C3 to maintain 5-selective C-halogen bond formation and tolerates a range of functional groups. This process accommodates pyridines embedded in complex structures, and thus has implications for drug and agrochemical development, where positional selectivity can greatly impact structure-activity relationship studies.