Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights

4-Aminopyridines
are valuable scaffolds for the chemical industry
in general, from life sciences to catalysis. We report herein a collection
of structurally diverse polycyclic fused and spiro-4-aminopyridines
that are prepared in only three steps from commercially available
pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an
ynamide, which constitutes the first examples of ynamides behaving
as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In
addition, running the ihDA/rDA reaction
in continuous mode in superheated toluene, to overcome the limited
scalability of MW reactions, results in a notable production increase
compared to batch mode. Finally, density functional theory investigations
shed light on the energetic and geometric requirements of the different
steps of the ihDA/rDA sequence.