Palladium-Catalyzed [3+2] Cycloaddition via Two-Fold 1,3-C(sp3)-H Activation

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 two-fold C(sp 3 )–H activation to generate the three-carbon unit for formal cycloaddition. The initial β-C(sp 3 )–H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp 3 )–H activation to complete a formal [3+2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp 3 )–H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to 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.