Understanding Catalyst Structure–Selectivity Relationships in Pd-Catalyzed Enantioselective Methoxycarbonylation of Styrene

Abstract

Catalyst-controlled regioselectivity in palladium-catalyzed carbonylation of alkenes has been a long-standing goal of homogeneous catalysis. In general, monophosphines do favor branched regioselectivity, but lead to poor enantioselectivity, while diphosphines give mainly linear products. Previously, we reported the simultaneous control of regio-and enantioselectivity in the hydroxy-and methoxycarbonylation of vinyl arenes with Pd complexes of the Phanephos ligand. Herein, we present a density functional theory study (B3PW91-D3 level of theory) of the catalytic cycle, supported by deuterium labeling studies, to understand its mechanism. Alkene coordination to a Pd-hydride species was identified as the origin of asymmetric induction and regioselectivity in both the parent Pd/Xylyl-Phanephos catalyst and electron-deficient analogue, and rationalized according to a quadrant-diagram representation. The mechanism by which the preferentially formed pro-(S) Pd-alkene complex can isomerize via rotation around the palladium-(C=C) bond was investigated. In the parent system, this process is in competition with the methanolysis step that leads to the ester product, and is responsible for the overall loss of regioselectivity. On the other hand, the introduction of electron-withdrawing substituents on the catalyst framework results in the reduction of the methanolysis barriers, making the isomerization pathway energetically unfavorable and so leading simultaneously to high regiocontrol and good enantiomeric ratios. ASSOCIATED CONTENT Supporting InformationThe Supporting Information is available free of charge on the ACS Publications website.Computational details, 2 H and 13 C NMR spectra, deuterium labeling studies (PDF)Cartesian coordinates, electronic energies, zero-point energies, enthalpies, T×S, Gibbs free energies, basis set superposition energies (a.u.), imaginary frequencies (XYZ)

Computational modelling of Pd-catalysed alkoxycarbonylation of alkenes and alkynes

“…Such interconversion is possible via a common intermediate 4-L (Scheme 4). 105 The isomerisation barrier of 17.9 kcal mol À1 at the Pd/(S)-Xylyl-Phanephos catalyst is lower than the isomerisation barrier of 21.0 kcal mol À1 at the Pd/(S)-F24-Phanephos catalyst, making the latter more selective than the former.…”

“…Gallarati et al performed mechanistic studies of Pdcatalysed methoxycarbonylation of styrene with chiral Phanephos diphosphines. 105 They demonstrated the effect of explicit solvation on the methanolysis barrier at the B3PW91-D3/6-311+G**/SDD/PCM level of theory. Their methanolysis barriers with similar schemes turned to be much lower than those we recently published for a different system.…”

Palladium‐Catalyzed Asymmetric Markovnikov Hydroxycarbonylation and Hydroalkoxycarbonylation of Vinyl Arenes: Synthesis of 2‐Arylpropanoic Acids

“…In general, similar mechanisms were considered for hydroxycarbonylation and hydroalkoxycarbonylation of alkenes because the broadly similar performances of a catalyst in both of the two reactions [22] . However, the mechanism of such reactions was involved in some debate between palladium carboalkoxy pathway (Scheme 2, Cycle I) and palladium hydride pathway (Scheme 2, Cycle II).…”

Palladium-catalyzed enantioselective carbonylation reactions

“…catalyst ((S)-2-2mo) was used in a two-step synthesis of (S)flurbiprofen methyl ester from commercially available 4bromo-2-fluoro-1,1′-biphenyl [8]. The reaction mechanism of this Pd/Phanephos-catalyzed methoxycarbonylation of styrene was investigated based on density functional theory (DFT) computations supported by the results of deuterium labeling studies [9]. Coordination of alkene to a Pd-hydride species was identified as the origin of asymmetric induction and regioselectivity and rationalized according to a quadrantdiagram representation.…”