Copper-mediated displacements of allylic THP ethers on a bisphosphonate template

Abstract

The copper-mediated displacement of allylic THP ethers by Grignard reagents has been examined in a system that contains a geminal bisphosphonate ester. With Grignard reagents derived from several aromatic halides or benzyl bromide the displacement proceeds in attractive yields, but more mixed results were obtained from reactions with alkyl halides. In addition to its role as a nucleophile, the Grignard reagent also appears to deprotonate the bisphosphonate to generate an anionic intermediate. Formation of this anion appears to limit competitive nucleophilic attack at the phosphonate group and provides an intermediate that can be trapped by reaction with an electrophilic reagent such as methyl iodide to access a more substituted system.