Click à la carte: robust semi-orthogonal alkyne protecting groups for multiple successive azide/alkyne cycloadditions

We herein describe an in-depth screening and systematic comparison of five classical silyl alkyne protective groups, to evaluate their potential in the context of multiple successive copper (I)-catalyzed alkyne–azide cycloadditions (CuAAC). We confirm the relative sensitivity of TMS, especially under CuAAC conditions. The relative robustness of its higher analogues, and the discovery of mild silver-catalyzed deprotection conditions selective for TES compared to DPS or TIPS allowed us to design a strategy allowing three successive CuAAC on a single scaffold, as we have illustrated by the synthesis of a tris-triazolo model compound.