Versatile Butenolide Syntheses via a Structure-Oriented C–H Activation Reaction

Abstract

Despite significant advances in forging a single bond via C–H activation in the past decade, one-step construction of biologically or chemically important scaffolds from abundant feedstock chemicals, namely, structure-oriented C–H activation, remains a significant challenge. Since feedstocks often contain a single functional group, multiple C(sp 3 )–H bond functionalizations are often necessary toward the assembly of densely functionalized scaffolds. As classic pharmacophores and versatile synthetic intermediates, butenolides have received extensive attention from the pharmaceutical industry and synthetic chemists. Here, we report the development of a palladium catalyst that enables the one-step conversion of aliphatic acids into ubiquitous butenolides involving triple functionalizations of methylene and methine C–H bonds with tert -butyl hydroperoxide (TBHP) as the sole oxidant. The unprecedented triazole–pyridone ligand is essential for realizing this “butenolide-oriented” C–H activation reaction. The availability of diverse aliphatic acids allows rapid access to unexplored but medicinally interesting chemical space of butenolides. Improved syntheses of a wide range of bioactive natural products and drug molecules were achieved using this reaction, including anticancer and anti-HIV compounds. As low as 1 mol % catalyst loading, ready scalability, and product purification through a simple aqueous washing represent rare practical advantages for C–H activation reactions.

Topics & Concepts