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Halogenation of the 3-position of pyridines through Zincke imine intermediates.

ABSTRACT: Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon-hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the nature of the halogen electrophile can modify the selectivity-determining step. Using this method, we produced a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

SUBMITTER: Boyle BT

PROVIDER: S-EPMC10631470 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Halogenation of the 3-position of pyridines through Zincke imine intermediates.

Boyle Benjamin T BT Levy Jeffrey N JN de Lescure Louis L Paton Robert S RS McNally Andrew A

Science (New York, N.Y.) 20221117 6621

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon-hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo h ...[more]

PMID: 36395214

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