Facile cleavage of the carbamate linker of hydroxymethyl resin and its application in syntheses requiring strongly acidic conditions

The carbamate linker of hydroxymethyl polystyrene is cleaved by treatment with a mixture of trifluoroacetic acid and dimethylsulfide at ambient temperature. The linker, an equivalent of Cbz, is stable to a wide range of acidic, basic, and reductive conditions. Fisher indole synthesis and Pictet–Spengler cyclization on solid support, which require 70°C in acetic acid with zinc chloride and 10% TFA in dichloromethane, respectively, were successfully carried out using this linker. The facile linker cleavage strategy enables more chemistry to be performed on hydroxymethyl polystyrene resin without recourse to HF.