Synthesis of Tetraazamacrocycles by Sequential Palladium-Catalyzed Allylic Substitution Reactions

Abstract

In this study, we focused on the synthesis of tetraazamacrocycles, an essential class of macrocyclic compounds with applications in coordination chemistry, pharmaceuticals, and catalysis. To accomplish this, we developed a ligand-controlled palladium-catalyzed allylic substitution approach using bicyclic bridgehead phosphoramidite (briphos) ligands. This approach allowed us to selectively achieve [1+1] and [1+2] allylic aminations between allylic diols and diamines, while avoiding the formation of cyclic [1+1] products. By combining this approach with sequential acetylation and allylic amination, we successfully synthesized tetraazamacrocycles with ring sizes ranging from 16 to 38. These findings demonstrate the potential of a sequential allylation strategy for synthesizing complex molecules with broad applications in the fields of chemistry, pharmaceuticals, and medicine.