Bronsted acid-catalyzed dynamic kinetic resolution of in situ formed acyclic N,O-hemiaminals: cascade synthesis of chiral cyclic N,O-aminals

A Bronsted acid-catalyzed cascade acyclic N,O-hemiaminal formation/oxa-Michael reaction is developed for the synthesis of cis-2,6-disubstituted tetrahydropyrans bearing an exo amide group, that is, cyclic N,O-aminals. By using TsOH, various different amides including carboxyamides, carbamates, sulfonamides and even phosphoramides were applicable for the designed reaction sequence. By using chiral phosphoric acid, a wide range of enantioenriched cyclic N,O-aminal scaffolds were obtained. Detailed mechanistic investigations revealed that the good enantioselectivity can be attributed to a H2O controlled dynamic kinetic resolution of the in situ formed acyclic N,O-hemiaminal intermediate during the reaction process. Furthermore, a number of divergent transformations of the obtained products were investigated, leading to various synthetically useful heterocyclic architectures.

Automated summary

In this study, a Bronsted acid-catalyzed cascade acyclic N,O-hemiaminal formation/oxa-Michael reaction was developed for the synthesis of cis-2,6-disubstituted tetrahydropyrans bearing an exo amide group, namely cyclic N,O-aminals. Various different amides were applicable for the reaction sequence using TsOH, and enantioenriched cyclic N,O-aminal scaffolds were obtained by using chiral phosphoric acid. Mechanistic investigations revealed that the good enantioselectivity was attributed to a H2O controlled dynamic kinetic resolution of the in situ formed acyclic N,O-hemiaminal intermediate. Additionally, divergent transformations of the products resulted in various synthetically useful heterocyclic architectures.