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

Abstract

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.

Synthesis of Chiral α-Aryl Ketones by Photoredox/Nickel-Catalyzed Enantioconvergent Acyl Cross-Coupling with Organotrifluoroborate

“…The transformation of 2-pyridyl ester , 4c can also be used as the acylating reagent to deliver acylation products. Acylating reagent S -(2-pyridyl)­thioester − 4d was found to be less reactive in this catalytic system, and no conversion of 4d was observed. This protocol was also ineffective in the transformation of phenolic ester 4e .…”

Nickel‐Catalysed Decarboxylative Coupling Reactions – An Overview

“…Another protocol for ketone synthesis was developed by Weix et al through the coupling of two activated carboxylic acid esters such as S-2-pyridyl thioesters132 and N-hydroxyphthalimide (NHP) esters 2. [63] They carried out the coupling reaction in presence of 2 mol % of NiBr 2 (dme), 2 mol % of bipyridine or terpyridine based ligand, Zn (2 equiv.) and ZnCl 2 (20 mol %) in DMA/THF solvent system to render diverse aryl-alkyl and alkyl-alkyl ketones 133 in high yields (Scheme 44).…”

Transition‐Metal Catalyzed Coupling Reactions for the Synthesis of (Het)aryl Ketones: An Approach from their Synthesis to Biological Perspectives

“…By using this approach, different alkyl ketones having various heterocyclic functionalities and different electron donating and withdrawing moieties have been synthesized (Scheme 68). Carbon‐carbon bond synthesis of ketones depends on two reagents one high availability reagent such as carboxylic acid and other low availability reagent such as organometallic or alkyl iodide etc [87] . A protocol has been developed which involves the coupling of N ‐hydroxyphthalimide esters and S ‐2‐pyridyl thioesters in presence of nickel catalyst which led to synthesis of the aryl alkyl and dialkyl ketones in significant yields.…”