Inverse Electron-Demand [4 + 2]-Cycloadditions of Ynamides: Access to Novel Pyridine Scaffolds

Functionalized polycyclic aminopyridines are central to the chemical sciences, but their syntheses are still hampered by a number of shortcomings. These nitrogenated heterocycles can be efficiently prepared by an intramolecular inverse electron demand hetero Diels−Alder (ihDA) cycloaddition of ynamides to pyrimidines. This ihDA/rDA sequence is general in scope and affords expedient access to novel types of aminopyridinyl scaffolds that hold great promise in terms of exit vector patterns.

We report an efficient method to prepare various fused aminopyridines and spiro-amino pyridines through the first inverse electron demand hetero Diels−Alder cycloadditions of ynamides. More than twenty original examples were obtained with good yields and the scale up of this method was efficiently obtained using flow chemistry. DFT computations allowed us to determine the pathway of the reaction and the kinetic determining step.