Modular Synthesis of Highly Substituted Pyridines via Enolate α‑Alkenylation

A novel methodology
for the synthesis of highly substituted pyridines
based on the palladium-catalyzed enolate α-alkenylation of ketones
is presented; the formation of aromatic compounds is a new direction
for this catalytic C–C bond forming reaction. In the key step,
a protected β-haloalkenylaldehyde participates in α-alkenylation
with a ketone to afford a 1,5-dicarbonyl surrogate, which then undergoes
cyclization/double elimination to the corresponding pyridine product,
all in one pot. The β-haloalkenylaldehyde starting materials
can be obtained from the corresponding methylene ketone via Vilsmeier
haloformylation. Using this concise route, a variety of highly substituted
pyridines were synthesized in three steps from commercially available
compounds.