Copper-Catalyzed C(sp 3 )-H α-Acetylation: Generation of Quaternary Centers

α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in natural products and pharmaceuticals. We report the α-acetylation of C(sp )-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH R at RT with BuOO Bu as...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2024-11, p.e202418692
Main Authors: Okoromoba, Otome E, Chen, Ting-An, Jang, Eun Sil, McMullin, Claire L, Cundari, Thomas R, Warren, Timothy H
Format: Article
Language:English
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Summary:α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in natural products and pharmaceuticals. We report the α-acetylation of C(sp )-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH R at RT with BuOO Bu as oxidant via copper(I) -diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [Cu ](CH C(O)Ar) that capture alkyl radicals R• to give R-CH C(O)Ar outcompeting dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH CH C(O)Ar.
ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.202418692