The tandem zinc-mediated chain extension-iodomethylation reaction and its applications

A tandem zinc-mediated chain extension-iodomethylation reaction was developed and used to generate various alpha-iodomethyl gamma-keto esters, amides and imides. The yields for formation of alpha-iodomethyl gamma-keto esters were higher than alpha-iodomethyl gamma-keto amides. beta-Keto amides with bulky substituents on the amide bond were not good substrates for the zinc-mediated chain extension-iodomethylation reaction. Use of a chiral beta-keto imide provided a facile means to effectively control the stereochemistry at the alpha-position of the extended chain with this methodology. A palladium-catalyzed cross-coupling reaction was used to install different functional groups at the alpha-carbon site of an -iodomethyl gamma-keto ester and imide. Reactions between alpha-iodomethylated gamma-keto compounds and aromatic iodides or an alkenyl bromide were performed successfully in modest yields. However, iodophenol and 1-fluoro-4-iodobenzene did not provide products when reacted with the alpha-iodomethylated product under the same reaction conditions. Other applications of the alpha-iodomethyl gamma-keto ester were studied in an effort to attach different alkyl groups to the alpha-position, including thiolation and nucleophilic alkylation. The alpha-substituted gamma-keto esters or imides can be designed to contain functionality that mimics the side chain of amino acids in a ketomethylene peptide isostere