Halogenated Reagents in the Ugi Reaction: From Rearrangement Reactions to Ketal Synthesis

The morpholine scaffold constitutes a privileged structural motif in medicinal chemistry, although access to conformationally restricted systems remains challenging. Herein, we report a simple and efficient Ugi/postcondensation strategy that, for the first time, combines two aliphatic halogenated reagents with arylglyoxals to afford fused and bridged morpholines bearing ketal functionalities in a diastereoselective manner. These derivatives serve as precursors to 4-hydroxypyroglutamic acid derivatives, highlighting the synthetic versatility of the approach and providing rapid entry to structurally complex heterocyclic derivatives.