Cyclization by C(sp³)–H Arylation with a Transient Directing Group for the Diastereoselective Preparation of Indanes

Abstract

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.

Pd(II)-Catalyzed Synthesis of Benzocyclobutenes by β-Methylene-Selective C(sp3)–H Arylation with a Transient Directing Group

“…This proposed mechanism is based on the presumption that Ag 3 PO 4 is first slowly converted to AgTFA before it operates as an iodide abstractor. 19 TS1-A is favored over TS1-B by 2.4 kcal/mol as a result of two contributing factors (Figure 2B). First, an attractive π−π interaction between the substrate arene and the pyridone ligand during CMD stabilizes the preferred TS1-A.…”

“…While previous reports have demonstrated that CMD under similar conditions is reversible, 19,69 calculations and an isotopic labeling study are consistent with accounts of mechanistic variations caused by small changes in the substrate. 70 In this case, the methylene selectivity may be due to two factors: (1) ligand−substrate interactions that promote methylene selectivity and (2) the geometry of Pd at the competing OA transition states.…”

“…BCB formation by reductive elimination (RE) from Pd(IV) has been shown in stoichiometric studies of organometallic palladium complexes but has proven to be elusive in catalysis. 16−18 We previously demonstrated a Pd(II/IV) system to achieve the synthesis of indanes, 19 and in the course of that study we sought to create benzo-fused carbocycles with different ring sizes using homologous iodoaryl ketones. As shown in Figure 1A, previous examples of monoprotected amino acid (MPAA)ligand-promoted intramolecular C(sp 2 )−H/C(sp 3 )−H coupling with a monodentate directing group (DG) revealed an exclusive reactivity pattern of methyl C(sp 3 )−H activation leading to six-membered tetralins.…”

“…This result is distinct from our earlier publication that described indane cyclizations by reversible CMD. 19 Work on broadening this result to achieve general ligand-controlled methylene selectivity is ongoing in our laboratory.…”

Transient Directing Groups in Metal−Organic Cooperative Catalysis

“…Eventually, the groups of Sorensen and Yu recently disclosed a palladium-catalyzed intramolecular version of a similar process, using glycine as the transient directing mediator and pyridinone ligands, enabling the intramolecular β-arylation of ketones bearing a remote iodoarene to indanes in high to excellent yields and high diastereoselectivity, accounted for a specific well-ordered and rigid Pd(II/IV) transition state (Scheme 66, g). [120] As for the mechanism of the C(sp 3 )À H (hetero)arylation of aliphatic aldehydes or ketones, the aforementioned processes using a transient imine directing group are believed to share the one depicted in Scheme 61, starting with aliphatic aldehydes and ketones instead of aromatic ones.…”