Pd/smNBE(D) Chemistry Meets the Amino Group: Catalytic Cycle and Chemoselectivity

ConspectusPalladium/norbornene (Pd/NBE) chemistry serves as a versatile strategy for the multifunctionalization of arenes, integrating the characteristics of both highly site-selective C-H functionalization and cross-coupling. In Pd(0)-initiated Pd/NBE chemistry using aryl halides as the substrate, the <i>ortho</i> substituent regulates the catalytic cycle through the "<i>ortho</i> effect" and "<i>ortho</i> constraint". The "<i>ortho</i> effect" reveals the critical role of the <i>ortho</i> substituent in governing the mechanistic pathways of <i>ortho</i> C-H functionalization and reductive elimination sites. Conversely, the "<i>ortho</i> constraint" refers to the perpendicular orientation of norbornene relative to the arene after initial C-H functionalization, facilitating β-carbon elimination to extrude norbornene. In the absence of an <i>ortho</i> substituent, the cycle favors dual C-H functionalization. Thus, both principles constitute the critical solution in Pd/NBE chemistry, requiring <i>ortho</i>-substituted aryl halides as substrates. That is why most reported applications of Pd/NBE chemistry in natural product and pharmaceutical synthesis leverage <i>ortho</i>-substituted haloarenes. Importantly, that the <i>ortho</i> position of haloarenes cannot tolerate an amino group is a long-recognized yet persistent limitation in Pd/NBE chemistry. This limitation arises primarily because the amino group's coordination ability and nucleophilicity disrupt the intricate catalytic cycle, precluding the formation of the desired C-H functionalized product.This account summarized our recent research on Pd/NBE(D) chemistry employing haloarenes with an amino group at the <i>ortho</i> position. We first described the use of steric hindrance to block direct C-N coupling of the norbornyl palladium species, thereby diverting the catalysis pathway to norbornene-mediated <i>ortho</i> C-H functionalization. Following this C-H functionalization, the system was poised to undergo an intramolecular C-N coupling/cyclization. Second, we described the utilization of inert C-N or N-S bond cleavage strategies to achieve highly selective extrusion of norbornene following norbornene-mediated C-H functionalization, which was then followed by migratory insertion of alkynes into the palladium intermediate and subsequent inert bond cleavage to construct C-N bonds. Third, we further addressed the challenge of how to prioritize the extrusion of norbornene via β-carbon elimination over the competing C-N bond coupling when a free N-H group was present at the <i>ortho</i> position of aryl halides after C-H functionalization. The aforementioned strategy was applicable to various C-H functionalizations, including amination, alkylation, arylation, glycosylation, acylation, and carbamoylation. In terms of the mechanism, density functional theory (DFT) calculations elucidated from multiple perspectives the mechanistic principles behind the high selectivity observed across different reaction pathways in the catalytic cycle. The synthetic utility of this method was validated through its application in the preparation of various important pharmaceutical agents and versatile building blocks.