Organic Chemistry

Programmed Heterocycle Synthesis Using Halomucononitriles as Zincke Nitrile Precursors



The isomeric imidazo[1,2-a]pyridines and pyrrolo[2,3-b]-pyridine (7-azaindole) heterocyclic cores are “privileged structures” due in part to their ability to interact with a multitude of different receptors, making them essential to the drug discovery process. Imidazo[1,2,-a]pyridine and 7-azaindole, though structurally related, are typically independently synthesized from 2-aminopyridine starting materials. Herein we report a method to convert primary amines, ubiquitous motifs found in pharmaceutical libraries, to either imidazo[1,2-a]pyridines or 7-alkyl azaindoles in two steps. Using halomucononitrile reagents, we can directly access 5-bromo-6-imino-1-alkyl-1,6-dihydropyridine-2-carbonitriles (pyridinimines) in a single step from primary amines (25–95% yield) through a cyclization of transient Zincke nitrile intermediates. We then demonstrate that these compounds can be readily converted to 7-alkylazaindoles using Sonogashira cross-coupling conditions (14 examples, up to 91% yield). Under oxidative conditions, the pyridinimines serve as directing groups for C–H functionalization reactions to afford imidazo[1,2-a]pyridines. We have studied the mechanism of the cyclization event using DFT calculations and propose this takes place via ketenimine intermediates.


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Supplementary material

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Supporting Information
1H NMR, 13C NMR, computational data and written procedures for study
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Supporting Information Continued
1H NMR, 13C NMR images