Ketone α-alkylation at the more-hindered site

Ming-Ming Li, Tianze Zhang, Lei Cheng, Wei-Guo Xiao, Jin-Tao Ma, Li-Jun Xiao () and Qi-Lin Zhou ()
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Ming-Ming Li: Nankai University
Tianze Zhang: Nankai University
Lei Cheng: Nankai University
Wei-Guo Xiao: Nankai University
Jin-Tao Ma: Nankai University
Li-Jun Xiao: Nankai University
Qi-Lin Zhou: Nankai University

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: Abstract Control of the regioselectivity of α-alkylation of carbonyl compounds is a longstanding topic of research in organic chemistry. By using stoichiometric bulky strong bases and carefully adjusting the reaction conditions, selective alkylation of unsymmetrical ketones at less-hindered α-sites has been achieved. In contrast, selective alkylation of such ketones at more-hindered α-sites remains a persistent challenge. Here we report a nickel-catalysed alkylation of unsymmetrical ketones at the more-hindered α-sites with allylic alcohols. Our results indicate that the space-constrained nickel catalyst bearing a bulky biphenyl diphosphine ligand enables the preferential alkylation of the more-substituted enolate over the less-substituted enolate and reverses the conventional regioselectivity of ketone α-alkylation. The reactions proceed under neutral conditions in the absence of additives, and water is the only byproduct. The method has a broad substrate scope and permits late-stage modification of ketone-containing natural products and bioactive compounds.

Date: 2023
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DOI: 10.1038/s41467-023-38741-w

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