Programmed Heterocycle Synthesis Using Halomucononitriles as Pyridinimine Precursors

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 from known
compounds. 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 (25–93% yield) through
the cyclization of transient aminomucononitrile intermediates. We
then demonstrate that these compounds can be readily converted to
7-alkylazaindoles using Sonogashira cross-coupling conditions (13
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 also studied
the mechanism of the cyclization event using DFT calculations and
propose that this takes place via sequential base-mediated E/Z isomerization and cyclization steps.