An organocatalyzed, formal (3+3)
cycloaddition reaction is described
for the practical synthesis of substituted pyridines. Starting from
readily available enamines and enal/ynal/enone substrates, the protocol
affords tri- or tetrasubstituted pyridine scaffolds bearing various
functional groups. This method was demonstrated on a 50 g scale, enabling
the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material
used for the manufacture of sotorasib. Mechanistic analysis using
two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed
the transformation proceeds through the reversible formation of a
stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR
studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.