Solid-phase synthesis of s-Tetrazines Zainab Alghamdi 1,2 , Maxime Klausen 1 , Alessia Gambardella 1 , Annamaria Lilienkampf 1 and Mark Bradley. 1 1 EaStCHEM School of Chemistry, University of Edinburgh, UK, 2 Department of Chemistry, Imam Abdulrahman Bin Faisal University, Saudi Arabia s -Tetrazines (1,2,4,5-tetrazines) stand out from the bioorthogonal toolbox with their superior reaction kinetics and high selectivity. s -Tetrazines selectively undergo inverse electron-demand Diels-Alder (IEDDA) reactions with dienophiles within complex biological systems, which has allowed for their use in various biological scenarios such as in sensing, imaging and drug delivery. 1–3 Despite the number of applications of s -tetrazines in bioorthogonal chemistry, their use has been significantly hampered by their laborious synthesis and purification. Here, we report an efficient solid-phase synthesis of various mono and disubstituted s- tetrazines. 4 This synthesis route was compatible with different solid-phase resins and linkers and did not require metal catalysts or high temperatures. Monosubstituted s- tetrazines were routinely synthesized using thiol-promoted chemistry, using dichloromethane as a carbon source, while disubstituted unsymmetrical aryl or alkyl tetrazines were synthesized using readily available nitriles. This efficient approach enabled the synthesis of s- tetrazines in high yields (70–94%), eliminating the classical solution-phase problems of mixtures of symmetrical and unsymmetrical tetrazines, with only a single final purification step required, and paves the way to the rapid synthesis of s- tetrazines with various applications in bioorthogonal chemistry and beyond. References 1. Nguyen, S. S.; Prescher, J. A. Nat. Rev. Chem. 2020 , 4 (9), 476-489. 2. Neuman, K.; Gambardella, A.; Lilienkampf, A.; Bradley M. Chem. Sci. 2018 , 9, 7198-7203. 3. Zhang, Y.; Üçüncü, M.; Gambardella, A.; Baibek, A.; Geng, J.; Zhang, S.; Clavadetscher, J.; Litzen, I.; Bradley, M.; Lilienkampf, A. J. Am. Chem. Soc. 2020 , 142 (52), 21615-21621 4. Alghamdi, Z. S.; Klausen, M.; Gambardella, A.; Lilienkampf, A.; Bradley, M. Solid-Phase Synthesis of s-Tetrazines. Org. Lett. 2023 , 17, 3104–3108
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