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Abstract

Based on versatile catalytic α,β-desaturation methods, strategies that directly functionalize carbonyl compounds at their less reactive β positions have emerged over the past decade. Among the established methods, the redox cascade strategy provides a distinct β-functionalization approach in a step-economical and redox-neutral manner. It is capitalized on reusing the Pd(0) species generated after α,β-desaturation in a subsequent carbon halogen bond activation, in which the electrophile serves as both the oxidant and the source for the β substituent, thus rendering an overall redox-neutral process. A direct β-alkenylation of simple ketones is disclosed via Pd-catalyzed redox cascade using readily available alkenyl bromides as the functionalization reagents. A wide range of sensitive functional groups are tolerated due to the mild reaction conditions, and the alkenylated ketone products can be diversely derivatized with various alkene transformations. In addition, coupling of ketones and aldehydes with simple alkyl bromides enables a direct β-alkylation approach, which has found synthetic applications in the synthesis of drug candidates. A copper cocatalyst is essential for enhanced efficiency through stabilizing radical intermediates and suppressing overoxidation. Finally, a formal addition of β-C-H bonds of ketones to alkynes is developed as a novel atom-economical approach for β-functionalization. Systematic mechanistic studies reveal a unique desaturation-mediated chain-like mechanism which features an intermolecular β-hydrogen transfer process.

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