Fluorous Synthesis with Fewer Fluorines (Light Fluorous Synthesis): Separation of Tagged from Untagged Products by Solid-Phase Extraction with Fluorous Reverse-Phase Silica Gel

Abstract

Fluorous synthesis involves tagging an organic substrate with a fluorinated tag for the purposes of separation. To date, techniques of fluorous synthesis have relied on liquid−liquid extractions. This paper applies a simple solid−liquid extraction procedure over fluorous reverse-phase silica gel (silica with a fluorocarbon bonded phase) for use in fluorous synthesis. Four amino acids were tagged on nitrogen with the C9F19CO− group, and the resulting acids were coupled in a parallel experiment with an excess of four amines. The resulting 16 crude fluorous amide products were separated from all the coupling reagents and excess amine by two-stage filtration through fluorous silica. In 15 of the 16 cases, the products were isolated in good to excellent yield and purity. All of the products are soluble in organic solvents and none is expected to have any significant solubility in fluorous solvents, so the experiment dramatically illustrates the advantages of the solid−liquid extraction over the liquid−liquid e...