DNA-Compatible <i>N</i>-Formylation of Amines by Using TMSCF₂Br

DNA-encoded libraries (DELs) have emerged as powerful tools in drug discovery. Protected amino acids serve as essential building blocks in the construction of DELs, resulting in the widespread presence of amino groups within these libraries. <i>N</i>-formylation of free amines not only enhances the activity of lead compounds but also functions as an effective amino-protecting strategy. In this study, we introduce trimethyl(bromodifluoromethyl)silane (TMSCF₂Br) as a novel <i>N</i>-formylation reagent for DEL synthesis. This approach demonstrates robustness in DEL-compatible synthesis and enables library diversification through functional group transformation (FGT). Additionally, we achieved efficient removal of formyl groups, enabling the formyl group to be strategically used for on-DNA amino protection orthogonal to Fmoc and Boc groups.