Computational Analysis of Enantioselective Pd-Catalyzed α-Arylation of Ketones

Abstract

The direct α-arylation of carbonyl compounds emerged over the last two decades as a straightforward method for the formation of C(sp 3 )–C(sp 2 ) bonds. Mechanistic studies suggested a classical cross-coupling catalytic cycle. This consists of oxidative addition of the aryl halide (ArX) to the Pd(0)-catalyst, transmetallation of the Na- or K-enolate generated in situ , and subsequent reductive elimination. Even though the general reaction mechanism was thoroughly investigated, studies focusing on enantioselective variants of this transformation are rare. Here, the computational study of the [Pd(BINAP)]-catalyzed α-arylation of 2-methyltetralone with bromobenzene is reported. The whole reaction energy profile was computed and several mechanistic scenarios were investigated for the key steps of the reaction, which are the enolate transmetallation and the C–C bond-forming reductive elimination. Among the computed mechanisms, the reductive elimination from the C-bound enolate Pd complex was found to be the most favorable one, providing a good match with the stereoselectivity observed experimentally with different ligands and substrates. Detailed analysis of the stereodetermining transition structures allowed us to establish the origin of the reaction enantioselectivity.

Insights into the Mechanism and Regioselectivity of Palladium-Catalyzed Arylation of α,β-Unsaturated Ketones

“…There are two mechanisms of the transmetallation step between Li-enolate and cis-[Pd(II)L 1 (Ar)(Cl)], one is classical four-membered ring transmetallation to provide the O-bound Pd-enolate, and the other is six-membered ring transmetallation to obtain the C-bound Pd-enolate. 23 Both INT3a and TS2a have lower free energy than INT3b and TS2b, which is 2.0 kcal/mol and 1.8 kcal/mol respectively. Although the free energies of the transmetallation products INT4a and INT4b are almost the same, comparing the two transition states, it is more inclined to the six-membered ring enolate palladium process in the transmetallation.…”

“…47 Based on previous studies, we proposed a catalytic cycle for the αand γ-arylation of α,β-unsaturated ketones (Scheme 2). [22][23][24] Due to the widespread synthetic utility of α,βunsaturated cyclic ketones fragment, 48 the p-chlorotoluene and isophorone experimentally employed were chosen as the model substrates in this theoretical calculation. Palladium acetate was first reduced by the phosphine ligand to zero-valent palladium complex A, [49][50][51] which was believed to be the catalytically active species in this catalytic system.…”

“…22 By comparing several modes of reductive elimination, Orlandi disclosed that the factors controlling the enantioselectivity of Pd-catalyzed αarylation of ketones were the electrostatic interaction and the steric repulsion in the reductive elimination step. 23 Recently, On Ying Yuen reported the first ligand control of Pd-catalyzed site-selective αand γ-arylation of α,βunsaturated ketones with aryl halides (Scheme 1b), and Li-Dong Shao reported the Pd-catalyzed γ-arylation of β-alkoxy cyclohexenones (Scheme 1c). 24,25 Through experimental mechanism investigations, they all observed that there was an H shift phenomenon during their reaction, and Shao proposed that it was mainly determined by the tunneling effect.…”

Palladium/TY‐Phos‐Catalyzed Asymmetric Intermolecular α‐Arylation of Aldehydes with Aryl Bromides

“…Since 1997, the Pd‐catalyzed direct α‐arylation of cyclic ketones was reported independently by Buchwald, Hartwig, and Miura, and this protocol [4] has been widely extended to enantioselective α‐arylation of other cyclic carbonyl compounds such as ketones, [3d, 5] lactone, [6] and amides [3e, 7] or lactam [8] . In addition, the mechanism was confirmed by Orlandi that the keys to the success of the reaction is the enolate transmetallation and C−C bond‐forming reductive elimination [5g] (Scheme 1 a). However, the asymmetric α‐arylation of acyclic carbonyl compounds to construct quaternary stereocenters has been much less explored due to the in situ generated Z / E ‐enolate intermediates leading to a pair of opposite enantiomers.…”

Palladium-Catalyzed Intramolecular Diarylation of 1,3-Diketone in Total Synthesis of (±)-Spiroaxillarone A

“…The overall reaction process involves Pd-catalyzed oxidative additions of aryl halides, trans-metalation of diketone enolates, and reductive elimination of alkyl/aryl-type σ Pd­(II) complexes. In this process, reductive elimination can be regarded as the rate-determining step . The calculations were performed at the B3LYP-D3/def2-TZVP/SMD//B3LYP-D3/def2-SVP level of theory.…”