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Nature. 2019 Mar;567(7748):373-378. doi: 10.1038/s41586-019-0926-8. Epub 2019 Jan 30.

Deacylative transformations of ketones via aromatization-promoted C-C bond activation.

Author information

1
Department of Chemistry, University of Chicago, Chicago, IL, USA.
2
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
3
College of Pharmacy, Army Medical University, Chongqing, China.
4
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA. pengliu@pitt.edu.
5
Department of Chemistry, University of Chicago, Chicago, IL, USA. gbdong@uchicago.edu.

Abstract

Carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds are the main constituents of organic matter. Recent advances in C-H functionalization technology have vastly expanded our toolbox for organic synthesis1. By contrast, C-C activation methods that enable editing of the molecular skeleton remain limited2-7. Several methods have been proposed for catalytic C-C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force4,6 or directing groups5,7 to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes5. Here we report a general C-C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.

PMID:
30758326
PMCID:
PMC6426660
[Available on 2019-07-30]
DOI:
10.1038/s41586-019-0926-8

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