Convenient Preparation of 4-Formyl-3,5-dimethoxyphenol and Its Incorporation into Linkers and Resins for Solid-Phase Synthesis

4-Formyl-3,5-dimethoxyphenol (1) is a key synthetic intermediate used to prepare the BAL family (backbone amide linker) of acid-labile linkers and resins. The utility of these linkers and resins for solid-phase synthesis of both peptides and non-peptides has been amply demonstrated. In this article we report a simple and scalable procedure for preparation of isomerically pure 4-formyl-3,5-dimethoxyphenol (1) and its subsequent incorporation into a representative BAL linker and functionalized resin: 4-(4-formyl-3,5-dimethoxyphenoxy)butanoic acid and 4-formyl-3,5-dimethoxyphenoxy-polystyrene, respectively. The procedures are reproducible, are readily scalable, and require no chromatography.