Rhodium-catalyzed regioselective C-H activation/Lossen rearrangement/annulation for the green synthesis of trisubstituted 2-pyridones

摘要

Multisubstituted 2-pyridones are prevalent in pharmaceuticals and bioactive molecules. We herein report an efficient and regioselective approach for the synthesis of trisubstituted 2-pyridone derivatives by a rhodium-catalyzed C-H activation/Lossen rearrangement/cyclization cascade reaction between acrylamides and propargyl alcohols. The desirable features of this protocol include a reusable catalytic system, high regioselectivity, uncommon Lossen rearrangement, good functional group tolerance, operation at room temperature, simple purification by filtration in most cases, and scale-up synthesis with as low as 1 mol% catalyst loading. Additionally, deuterium labeling and KIE assays were performed to investigate the reaction mechanism. The vital effect of the hydroxyl group on propargyl alcohols in determining the regioselectivity was demonstrated by control experiments and DFT calculations. In addition, Mulliken atomic charge analysis of the key intermediates was also carried out to probe the origin of the observed preference for the Lossen rearrangement.

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