Hydrogen Fluoride\nImidazole: A Simple, Efficient,\nMild, and Cost-Effective Silyl-Ether Deprotection Reagent

Despite the availability of numerous −OH silyl\nprotection\nand deprotection methods, the selective cleavage of silyl ethers in\nhighly complex molecules can still be a challenge. In this article,\nwe present results from a full investigation of a novel, efficient,\nand mild desilylation protocol using HF/imidazole. Imidazole significantly\nenhances the desilylation reaction efficiency of HF, allowing clean\nand complete deprotection of TBDPS ethers in substrates containing\nboth acid and base sensitive groups. For example, four- and five-mer\noligonucleotides were efficiently deprotected where all other conditions\nfailed. HF/imidazole is also an effective reagent for the deprotection\nof TIPS and TBDMS ethers. The reagent prepared using commercially\navailable HF and imidazole maintained the same reactivity even after\n4 years of storage at 4 °C. Residual reagents and byproducts\ncan be readily removed with a simple workup; consequently, deprotection\nof TBDPS was successfully implemented in a 2.5 kg scale synthesis\nof a five-mer oligonucleotide.