Site-selective functionalization of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, developing strategies to activate C–H bonds that are distal from a functional group is essential. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukemia agent, and hydrocinnamic acid substrates.

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Expanded helicenes are large, structurally flexible π-frameworks that can be viewed as building blocks for more complex chiral nanocarbons. Here we report a gram-scale synthesis of an alkyne-functionalized expanded [11]­helicene and its single-step transformation into two structurally and functionally distinct types of macrocyclic derivatives: (1) a figure-eight dimer via alkyne metathesis (also gram scale) and (2) two arylene-bridged expanded helicenes via Zr-mediated, formal [2+2+n] cycloadditions. The phenylene-bridged helicene displays a substantially higher enantiomerization barrier (22.1 kcal/mol) than its helicene precursor (<11.9 kcal/mol), which makes this a promising strategy to access configurationally stable expanded helicenes. In contrast, the topologically distinct figure-eight retains the configurational lability of the helicene precursor. Despite its lability in solution, this compound forms homochiral single crystals. Here, the configuration is stabilized by an intricate network of two distinct yet interconnected helical superstructures. The enantiomerization mechanisms for all new compounds were probed using density functional theory, providing insight into the flexibility of the figure-eight and guidance for future synthetic modifications in pursuit of non-racemic macrocycles.

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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.