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(sp³)-C(sp²) 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.

Figure 1

(a) Catalytic cycle of the α-arylation of carbonyl compounds. (b) Possible pathways for the reductive elimination step. (c) Benchmark reaction investigated in this study.

Figure 2

Reaction Gibbs free energy profile (kcal/mol) of the enantioselective α-phenylation of 2-methyltetralone 4a catalyzed by [Pd((R)-BINAP)] at the [CPCM = toluene]PBE/SDD:6-311+G(d,p)//PBE/lanl2dz:6-31G(d) level of theory. Different reaction pathways are highlighted in different colors (see the pathway color legend).

Figure 3

Computed ΔΔG^⧧ values in kcal/mol and geometric features for the reaction with different ligand/substrate combinations at the [CPCM = toluene]PBE-D3/SDD:6-311+G(d,p)//PBE/lanl2dz:6-31G(d) level of theory. (a) (R)-BINAP/4a, (b) (R)-Difluorphos/4a, and (c) (R)-BINAP/4b. The phenyl and enolate ligands undergoing C–C bond formation are highlighted in green. C–H···O NCIs are highlighted as black dotted lines and their values are reported in Å. All of the hydrogen atoms not involved in highlighted interactions are omitted for clarity.

Figure 4

Energy decomposition analysis for the evaluation of the contributions affecting the reaction selectivity at the TS level. (a) General concept and evaluation of the NCI contribution given by the whole ligand. (b) Analysis of the NCI contributions given by each one of the ligand phenyl substituents.

Figure 5

Detail of the structures TS_RECS and TS_RECS^dif, showing steric repulsion between the γ-methylene group of 4a and Ph2/Ph3 in the ligand. The phenyl and enolate portions undergoing C–C bond formation are highlighted in green. H···H distances are highlighted as black dotted lines and their values are reported in Å. Hydrogen atoms not involved in highlighted interactions are omitted for clarity.