One-Step Synthesis of β-Alkylidene-γ-lactones via Ligand-Enabled β,γ-Dehydrogenation of Aliphatic Acids

Ligand-enabled Pd-catalyzed regioselective alpha,beta-dehydrogenation of carbonyl compounds via beta-methylene C-H activation has recently emerged as a promising transformation. Herein, we report the realization of beta,gamma-dehydrogenation and subsequent vinyl C-H olefination reactions of free carboxylic acids, thus providing a unique method for the structural diversification of aliphatic acids containing alpha-quaternary centers through sequential functionalizations of two beta-C-H bonds and one gamma-C-H bond. This tandem dehydrogenation-olefination-lactonization reaction offers a one-step preparation of beta-alkylidene-gamma-lactones, which are often difficult to prepare through conventional methods, from inexpensive and abundant free aliphatic acids. A variety of free aliphatic acids, such as isosteviol and grandiflorolic acid natural products, and olefins are compatible with the reported protocol. The newly designed bidentate oxime ether-pyridone and morpholine-pyridone ligands are crucial for this tandem reaction to proceed. Notably, these ligands also enable preferential methylene C-H activation over the previously reported, competing process of methyl C-H bond olefination.

Automated summary

The study presents a novel method for the dehydrogenation-olefination-lactonization of aliphatic acids, providing a unique approach to diversify structures. The use of newly designed bidentate ligands is crucial for the success of this tandem reaction, enabling preferential methylene C-H activation.