Synthesis of the C À Cb onds of ketones relies upon one high-availability reagent (carboxylic acids) and one lowavailability reagent (organometallic reagents or alkyliodides). We demonstrate here ak etone synthesis that couples two different carboxylica cid esters,N -hydroxyphthalimide esters and S-2-pyridyl thioesters,t of orm aryl alkyl and dialkyl ketones in high yields.The keys to this approach are the use of anickel catalyst with an electron-poor bipyridine or terpyridine ligand, aT HF/DMA mixed solvent system, and ZnCl 2 to enhance the reactivity of the NHP ester.The resulting reaction can be used to form ketones that have previously been difficult to access,s uch as hindered tertiary/tertiary ketones with strained rings and ketones with a-heteroatoms.The conditions can be employed in the coupling of complex fragments, including a2 0-mer peptide fragment analog of Exendin(9-39) on solid support. Scheme 1. Strategies in ketone synthesis.

A new strategy for the synthesis of ketones is presented based upon the decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with S-2-pyridyl thioesters. The reactions are selective for the cross-coupled product because NHP esters act as radical donors and the thioesters act as acyl donors. The reaction conditions are general and mild, with over 40 examples presented, including larger fragments and the 20-mer peptide Exendin(9-39) on solid support.

While the coupling of carboxylic acid derivatives to form new C-N and C-O bonds is a staple of organic synthesis and has been automated, the synthesis of the C-C bonds of ketones generally requires the use of reactive organometallic reagents incompatible with many functional groups. We demonstrate here a new approach to ketone synthesis that couples two different carboxylic acid esters, N-hydroxyphthalimide esters (NHP esters) and S-2-pyridyl thioesters (SPy esters), to form aryl-alkyl and dialkyl ketones in high yields. The keys to the approach are the use of a nickel catalyst with an electron-poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl2 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 heterocycles. The conditions can be employed in the coupling of complex fragments, including a 20-mer peptide, an analogue of Exendin(9-39), on solid support. carboxylic acid esters. These first-generation conditions are already competitive with the best available methods and are particularly well-suited to challenging ketones, such as those with severe steric hinderance and those that incorporate heterocycles. The versatility of the method could even be extended to the coupling of larger, functionalized fragments, including peptides on solid support. Further improvements are underway, including one-pot methods, alternative substrate pairs, and expanding the types of ketones that can be synthesized. ASSOCIATED CONTENTSupporting Information. Detailed experimental procedures, supplementary optimization data, characterization data for all isolated products, and copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

A new strategy for the synthesis of ketones is presented based upon the decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with S-2-pyridyl thioesters. The reactions are selective for the cross-coupled product because NHP esters act as radical donors and the thioesters act as acyl donors. The reaction conditions are general and mild, with over 40 examples presented, including larger fragments and the 20-mer peptide Exendin(9-39) on solid support.