Unveiling the Mechanism, Origin of Stereoselectivity, and Ligand-Dependent Reactivity in the Pd(II)-Catalyzed Unbiased Methylene C(sp³)–H Alkenylation–Aza-Wacker Cyclization Reaction

Abstract

The mechanism, origin of stereoselectivity, and ligand-dependent reactivity of Pd(II)-catalyzed methylene C(sp 3 )−H alkenylation−aza−Wacker cyclization to form (E)-β-stereogenic γ-lactam have been comprehensively studied by density functional theory (DFT) calculations. The calculated results reveal that the methylene C−H activation assisted by K 2 CO 3 via the concerted metalation− deprotonation mechanism is found to be the most preferred pathway, where the enantioselectivity is distinguished by the orientation of the methyl group of a substrate relative to a chiral ligand. However, the stereochemistry of the olefin moiety in the generated product is mainly determined by the oxidative addition step, where the coulombic interaction and dispersion effect differentiate the energy difference of diastereomeric transition states. In terms of the agostic interaction nature of "three-center two-electron" transition states, the discrepancy of reactivities caused by different Pd catalysts is attributed to the electron induction effect of substituents on the chiral ligands. In other words, the use of an electron-withdrawing group (e.g., −CN) in place of an electron-donating group (e.g., −OMe) enhances the oxidation state of the Pd atom and lowers vacant d orbitals of the palladium atom of the catalyst and in turn facilitates a larger amount of σ-electronic-charge injection into an empty 3d shell of the palladium center. Thus, the higher catalytic activity of the Pd catalyst with ligands substituted by an electron-withdrawing group is anticipated.

Recent Advances in the Synthesis of Five‐membered Nitrogen Heterocycles Induced by Palladium Ions and Complexes

“…Guo, Li et al . also explored the mechanism of the above transformation [38] . Their DFT calculation revealed that a concerted metalation−deprotonation mechanism assisted by K 2 CO 3 was the most preferred pathway determining rate and enantioselectivity.…”

“…[37] Guo, Li et al also explored the mechanism of the above transformation. [38] Their DFT calculation revealed that a concerted metalation À deprotonation mechanism assisted by K 2 CO 3 was the most preferred pathway determining rate and enantioselectivity. According to their results, enantioselectivity arose from the relative orientation of the substrate methyl group and the phenyl group of the chiral ligand.…”

Synthesis of N-Tosyl Allylic Amines from Substituted Alkenes via Vanadoxaziridine Catalysis

“…Interestingly, most of these rely on the formation of metal nitrenoids in the form of metal imido or nitrene intermediates to achieve the activation process . On the other hand, transition metal activation followed by nitrogen addition and Wacker-type oxidative processes have also received significant attention . Moreover, metal-free methods involving formal C–H functionalization have also been studied (Figure ).…”

“… 5 On the other hand, transition metal activation followed by nitrogen addition and Wacker-type oxidative processes have also received significant attention. 6 Moreover, metal-free methods involving formal C–H functionalization have also been studied ( Figure 1 ). 7 These reactions have become ubiquitous in organic chemistry to the extent of being extensively used in late-stage functionalization of complex molecules and in many total syntheses.…”