A Stepwise Approach to 1,4,10,13-Tetraaza-18-Crown-6 Ether

A two-step approach to the synthesis of tetraaza-18-crown-6 ether was evaluated to address the limitations of the currently used one-step macrocyclization, such as low yield due to substantial side product formation. In this route, the reaction conditions were optimized, reducing cyclization to the undesired nine-membered ring by a factor of eight. This resulted in a 50% yield for the two-step macrocyclization, or 28% when column chromatography was avoided, both significantly higher than the 16% yield obtained when reproducing the one-step method.