Methylene-selective C-H functionalization is a significant hurdle that remains to be addressed in the field of Pd(II) catalysis. In this paper we report a Pd(II) catalyzed synthesis of benzocyclobutenes by methylene-selective C(sp 3 )-H arylation of ketones using a transient directing group. The reaction utilizes glycine as a transient directing group and an electron poor pyridone ligand which is expected to promote concerted metallation deprotonation, but also controls methylene selectivity by intimate interactions with the substrate. These reaction conditions are shown to be highly selective for intramolecular methylene C(sp 3 )-H arylation, and thus enable sequential C(sp 3 )-H functionalization.

We report Pd(II)-catalyzed cyclative C(sp 3 )−H arylation of ketones with a transient directing group (TDG). Based on calculations, the oxidative addition step implicates a highly strained trigonal bipyramidal geometry around a Pd(IV) intermediate afforded by the bidentate TDG and the intramolecular arylation process. As a consequence, unproductive protodeiodination outcompetes the cyclative arylation Pd(II/IV) pathway under standard conditions. The desired selectivity was achieved by prudent selection of the TDG and the Ag(I) source. The reaction is accelerated by the inclusion of stoichiometric quantities of trifluoroacetic acid, which benefits both the palladium catalysis and the attachment of the TDG for the pivotal C(sp 3 )−H palladation. Critically, the use of the 2-pyridone ligand improves yields significantly and enables the cyclative arylation of both methyl and linear methylene C−H bonds. Mechanistically, the high energy barrier associated with the transition state of this cyclization type is sufficient to drive selective linear methylene C−H activation in the presence of a more reactive methyl C−H bond. The reaction is showcased in a two-step synthesis of a substituted indane using 3-iodoanisole as the linchpin in a formal [3 + 2] annulation concept featuring two C(sp 3 )−H arylations.

An 8-step synthesis of a known pentacyclic intermediate toward the natural product pleurotin (1) is described. Pleurotin and related benzoquinone natural products are of great interest for their powerful anticancer and antibiotic activities. The route features a regio- and diastereoselective intermolecular photoenolization/Diels–Alder cycloaddition and an alkoxy-radical-induced hydrogen atom transfer-mediated C–H epimerization to construct pleurotin’s carbon framework with appropriate relative stereochemical relationships. The synthesis concludes with a ring-forming benzylic C–H oxidation to deliver oxepane 19.

Methylene-selective C‒H functionalization is a significant hurdle that remains to be addressed in the field of Pd(II) cataly-sis. In this paper we report a Pd(II) catalyzed synthesis of benzocyclobutenes by methylene-selective C(sp3)‒H arylation of ketones using a transient directing group. The reaction utilizes glycine as a transient directing group and an electron poor pyridone ligand which is expected to promote concerted metallation deprotonation, but also controls methylene selectivity by intimate interactions with the substrate. These reaction conditions are shown to be highly selective for in-tramolecular methylene C(sp3)‒H arylation, and thus enable sequential C(sp3)‒H functionalization.

An 8-step synthesis of a known pentacyclic intermediate towards the natural product pleurotin (1) is described. Pleurotin and related benzoquinone natural products are of great interest for their powerful anticancer and antibiotic activities. The route features a regio- and diastereoselective intermolecular Diels-Alder cycloaddition and an alkoxy-radical-induced HAT-mediated C–H epimerization to construct pleurotin’s carbon framework with appropriate relative stereochemical relationships. The synthesis concludes with a ring-forming benzylic C–H oxidation to deliver oxepane 19.