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. 2020 Aug 3;59(32):13484-13489.
doi: 10.1002/anie.202002271. Epub 2020 Jun 5.

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids

Jiang Wang  1 , Megan E Hoerrner  2 , Mary P Watson  2 , Daniel J Weix  1
Affiliations

Nickel-Catalyzed Synthesis of Dialkyl Ketones from the Coupling of N-Alkyl Pyridinium Salts with Activated Carboxylic Acids

Jiang Wang et al. Angew Chem Int Ed Engl. .

Abstract

While ketones are among the most versatile functional groups, their synthesis remains reliant upon reactive and low-abundance starting materials. In contrast, amide formation is the most-used bond-construction method in medicinal chemistry because the chemistry is reliable and draws upon large and diverse substrate pools. A new method for the synthesis of ketones is presented here that draws from the same substrates used for amide bond synthesis: amines and carboxylic acids. A nickel terpyridine catalyst couples N-alkyl pyridinium salts with in situ formed carboxylic acid fluorides or 2-pyridyl esters under reducing conditions (Mn metal). The reaction has a broad scope, as demonstrated by the synthesis of 35 different ketones bearing a wide variety of functional groups with an average yield of 60±16 %. This approach is capable of coupling diverse substrates, including pharmaceutical intermediates, to rapidly form complex ketones.

Keywords: acyl fluorides; cross-coupling; ketone synthesis; nickel; pyridinium Salts.

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Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

Figures

Scheme 1.
Scheme 1.
How to make ketones from amine and carboxylic acid derivatives.
See this image and copyright information in PMC

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