Hydrogen Fluoride Imidazole: A Simple, Efficient, Mild, and Cost-Effective Silyl-Ether Deprotection Reagent

Abstract

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