Abstract
Cytochrome P450 enzymes are known to catalyze bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation5,6. Developing analogous catalytic systems for remote C−H functionalization remains a significant challenge14,15,16. Here we report the development of Cu(I)-catalyzed bimodal dehydrogenation/lactonization reactions of synthetically common N-methoxyamides via radical abstractions of the γ-aliphatic C−H bonds. The feasibility of switching from dehydrogenation to lactonization has also been demonstrated by altering reaction conditions. The use of a readily available amide as both radical precursor and internal oxidant allowed for the development of a redox-neutral C−H functionalization reactions with methanol as the sole side product. These C−H functionalization reactions using Cu(I) catalyst of loading as low as 0.5 mol% have been applied to the diversification of a wide range of aliphatic acids including drug molecules and natural products. The exceptional compatibility of this catalytic system with a wide range of oxidatively sensitive functionality demonstrates the unique advantage of using simple amide substrate as the mild internal oxidant.
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This file contains Supplementary Figures S1-19; Supplementary Tables S1-8 and Supplementary References.
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Zhou, S., Zhang, ZJ. & Yu, JQ. Copper-catalyzed dehydrogenation or lactonization of C(sp3)−H bonds. Nature (2024). https://doi.org/10.1038/s41586-024-07341-z
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DOI: https://doi.org/10.1038/s41586-024-07341-z
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