En Route to Ketones

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The research group of Professor Jin Xie at Nanjing University have being focusing on developing photoredox phosphoranyl radical chemistry for redox potential independent deoxygenation of carboxylic acids in the past two years. We have developed a general deoxygenation approach for synthesis of a wide range of structurally diverse ketones and aldehydes from carboxylic acids (Nature Commun. 2018, 9, 3517; Angew. Chem. Int. Ed. 2019, 58, 312; Chem. Eur. J. 2019, 25, 12724). Very recently, we have developed a novel cross-electrophile coupling between aromatic carboxylic acids and organic halides via photoredox and a nickel and phosphoranyl radical synergistic combination, affording a wide array of structurally diverse ketones with excellent functional group compatibility (Nature Commun. DOI:10.1038/s41467-020-17224-2).

The skeleton of ketones plays an important role in organic chemistry field due to its moiety is extremely common in natural products and pharmaceuticals and in dyes, fragrances. We posited that a carboxylic acid could be directly used as a latent electrophile (C-terminus) rather than a nucleophile (O-terminus) in cross-coupling enabled by photoredox catalysis, nickel and phosphoranyl radical chemistry. However, the use of free carboxylic acids as acyl radical precursors is a challenge in the oxidative addition step as a result of the strong bond dissociation energy of the C–O bond (106 kcal mol1). This method could simplify and upgrade ketone synthesis from carboxylic acids and organic halides. This method also shows high selectivity, low loading of nickel catalyst and ligand, generally good yields, mild reaction conditions, good functional group tolerance and broad substrate scope, providing great potential for the synthesis of ketones. This strategy for ketone synthesis can significantly improve the synthetic efficiency and step-economy, and it also opens a door to construct highly functionalized or complex ketones which are still difficult to prepare by a conventional Weinreb ketone synthesis.

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Jin Xie

PI, Nanjing University

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