<div>Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) are required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3+2] reaction that utilizes C(sp<sup>3</sup>)–H activation to generate the three-carbon unit for formal cycloaddition with maleimides. We implemented a strategy where the initial C(sp<sup>3</sup>)–H activation/olefin insertion would trigger a relayed, second remote C(sp<sup>3</sup>)–H activation to complete a formal [3+2] cycloaddition. The diastereoselectivity profile of this reaction resembles that of a typical pericyclic cycloaddition reaction in that the relationships between multiple stereocenters are exquisitely controlled in a single reaction. The key to success was the use of weakly coordinating amides as the directing group, as undesired Heck or alkylation pathways were preferred with other types of directing groups. The use of the pyridine-3-sulfonic acid ligands is critical to enable C(sp<sup>3</sup>)–H activation directed by this weak coordination. The method is compatible with a wide range of amide substrates, including lactams, which lead to novel spiro-bicyclic products. The [3+2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.</div>
Palladium-Catalyzed [3+2] Cycloaddition via Two-Fold 1,3-C(sp3)−H Activation