Copper-catalyzed dehydrogenation or lactonization of C(sp³)−H bonds

Abstract

Cytochrome P450 enzymes are known to catalyze bimodal oxidation of aliphatic acids via radical intermediates, which partition between pathways of hydroxylation and desaturation^5,6. Developing analogous catalytic systems for remote C−H functionalization remains a significant challenge^14,15,16. 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.