Five-Membered Nitrogen Heterocycles Synthesis through 1,3-Dipolar Cycloaddition of Non-Stabilized Azomethine Ylides with 2-Pyridone Heteroaromatic Systems as Dipolarophiles

We report an efficient 1,3-dipolar cycloaddition involving non-stabilized electron-rich azomethine ylides and diversely substituted 2-pyridones bearing two potential C=C dipolarophilic sites. The 1,3-dipoles were prepared in situ under TFA catalysis and cycloadditions were studied according to the nature of the pyridones and position of the various substituents. These reactions occur under mild conditions, and lead to the expected cycloadducts in good yields and full control of the regioselectivity. Furthermore, mono- or biscycloadditions were performed, leading to the formation of polycyclic scaffolds bearing biologically relevant pyrrolidine rings, prevalent in natural products. The diastereoselectivity of the second cycloaddition was fully controlled by the first addition, leading to heterocycles with a trans relative stereochemistry of the two generated rings in the final tricyclo-adduct.

Automated summary

An efficient 1,3-dipolar cycloaddition was reported, involving non-stabilized electron-rich azomethine ylides and diversely substituted 2-pyridones bearing two potential C=C dipolarophilic sites. The reactions occur under mild conditions, leading to the expected cycloadducts with good yields and full control of the regioselectivity. Furthermore, the diastereoselectivity of the second cycloaddition was fully controlled by the first addition, resulting in tricyclo-adducts with a trans relative stereochemistry.