Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters.

Synthesis of the C-C bonds of ketones relies upon one high-availability reagent (carboxylic acids) and one low-availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N-hydroxyphthalimide esters and S-2-pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron-poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α-heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20-mer peptide fragment analog of Exendin(9-39) on solid support.