Direct sp3 C-H functionalization to form new C-C bonds represents an attractive strategy to expand access to new synthetic space containing both simple and complex organic molecules. Employing catalysts based on earth abundant copper, we will discuss our approach that involves radical relay catalysis to generate new C-C bonds. Initially focusing on C(sp3)-C(sp3) bond formation, we outline a system utilizing di-tert-butyl peroxide that generates versatile [CuII]-OtBu intermediates. Acid-base reactions with substrates possessing mildly acidic a-C-H bonds such as acetophenone give reactive [CuII](enolate) intermediates. These copper(II) enolates capture alkyl radicals formed via H-atom abstraction of sp3 C-H substrates R-H by t-butoxy radical to give a-alkylated ketones. The radical nature of this reaction enables the formation of crowded 4° carbon centers difficult to form via electrophile-nucleophile pathways. DFT studies support synthetic studies that reveal that the copper(II) enolate intermediate can capture alkyl radical, and also it may dimerize to form 1,4-diketones. Exploratory studies also reveal that related copper(II) organometallic intermediates can be exceptionally reactive towards H-atom abstraction from sp3 C-H bonds, opening up new mechanistic opportunities for C-C bond formation via sp3 C-H functionalization.

Copper catalyzed sp3 C-H functionalization for C-C bond formation

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ACS Fall 2022

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