Easy access to medium-sized lactones through metal carbene migratory insertion enabled 1,4-palladium shift

Abstract

Reactions that efficiently construct medium-sized lactones are significant, as they overcome the unfavorable entropic factor and transannular interactions for ring closure, and the lactones produced are common structural motifs recurring in many biologically active compounds. Herein, we describe a valuable strategy for medium-sized lactone synthesis by accomplishing site-selective C-H bond functionalization via a palladium carbene migratory insertion enabled 1,4-palladium shift. The overall process achieves the formal dimerization of two readily available benzaldehyde derivatives, providing value-added products mediumsized lactones. Our method is amenable to late-stage modification of approved drugs and other complex molecules. Mechanistic studies including deuterium-labeling experiments and DFT calculation shed light on the reaction pathways.

A Modular Approach to Dibenzo‐fused ϵ‐Lactams: Palladium‐Catalyzed Bridging‐C−H Activation

“…These experiments explained the origin of hydrogen atoms on the central ring. Collectively, the data obtained here are in agreement with our initial mechanistic hypothesis, which involves metal carbene migratory insertion enabled 1,4‐palladium shift (Scheme ) …”

Marine furanocembranoids-inspired macrocycles enabled by Pd-catalyzed unactivated C(sp3)-H olefination mediated by donor/donor carbenes

“…Accordingly, these reactions are distinguished by their high stereoselectivity and wide substrate scope including several drug derivatives. DFT mechanistic studies reveal that a formal 1,4-Pd shift could be involved 23 , 51 – 58 . The unique features of these alkene substituted furans are illustrated as building blocks for the construction of anti-inflammatory 59 macrocyclic targets.…”

Recent Advances in Palladium-Catalyzed Bridging C–H Activation by Using Alkenes, Alkynes or Diazo Compounds as Bridging Reagents

“…Scheme 32 Palladium-catalyzed medium-sized lactone synthesis via carbene bridging C-H bond activation Encouraged by the aforementioned work, Huang and co-workers applied their CBA strategy for the synthesis of seven-and eight-membered lactones. 60 As demonstrated in Scheme 32, N-tosylhydrazones 145 derived from salicylaldehyde analogs were selected as the precursors of bifunctional diazo compounds to react with benzaldehydes 73. This reaction displayed very broad substrate scope.…”