Constructing ubiquitous bridged bicyclic scaffolds from simple aliphatic feedstocks via multiple C(sp3)–H functionalizations is a significant challenge in organic synthesis, demanding powerful catalysts capable of precise selectivity control. Here we demonstrate a catalytic system that enables abundant cyclic carboxylic acids to couple with dienophiles in a formal Diels–Alder manner with exclusive regioselectivity, forging bridged bicyclic scaffolds. Mechanistic studies revealed that the pyridine–pyridone ligand plays a crucial role in the β,γ-dehydrogenation of cyclic carboxylic acids, concerted decarboxylation process and subsequent regioselective β-hydride elimination through precise control of the electronic distribution of palladium and cyclic carboxylic acids and the steric interactions between them. Dienes generated in situ are rapidly intercepted by a variety of dienophiles, furnishing the bridged bicyclic motifs with exclusive endoselectivity. Notably, β-, γ- and δ-methylene C(sp3)–H bonds are functionalized with exclusive regioselectivity controlled by one catalyst. Bridged bicyclic frameworks are valuable in medicinal chemistry but difficult to access from simple saturated precursors. In situ generation of cyclic 1,3-dienes from unactivated carboxylic acids remains challenging. Now it has been shown that ligand-guided Pd(II) C–H activation enables multi-step diene formation for highly selective formal Diels–Alder reactions.
He et al. (Fri,) studied this question.