Equipping 1,4,7-Triazacyclononane with Substituents via Solid-Phase Synthesis

Metal ion complexes frequently show substituted 1,4,7-triazacyclononane (tacn) as the ligand. Besides providing donor atoms for complex formation, tacn serves as a scaffold for equipping the complex with further functional units that are needed for the complementation and electronic tuning of the metal ion coordination sphere and/or add other features, e.g., light-absorbing antennas and groups for bioconjugation. To exploit the full potential of substituted tacn, strategies for directed syntheses of NO(R¹,R¹,R²) and NO(R¹,R²,R³), i.e., tacn with two and even three different substituents R, are needed. Herein, we report a strategy that takes advantage of solid-phase synthesis in the assembly of the precursors NO(R¹,R¹,H) and NO(R¹,R²,H). The assembly of NO(R¹,R²,H) is based on a highly selective formation of NO(Cbz,tfAc,H), with Cbz being the link between tacn and solid phase. For this, tacn was loaded onto (4-nitrophenyl carbonate)-resin, thereby forming resin-bound (rb)-tacn, which corresponds to NO(Cbz,H,H) bound to the solid phase. Treatment of rb-tacn with ethyl trifluoroacetate gave rb-NO(tfAc,H), which corresponds to NO(Cbz,tfAc,H). With rb-tacn and rb-NO(tfAc,H) in hand, a variety of NO(R¹,R¹,H) and NO(R¹,R²,H) were prepared, showing the broad applicability of the strategy with respect to the type of substituents and of reactions (nucleophilic substitution, reductive amination, aza-Michael addition, addition to epoxides, acylation). The study also identified limitations and points for improvement.