Advancing the mechanistic understanding of an enantioselective palladium-catalyzed alkene difunctionalization reaction

Abstract

The mechanism of an enantioselective palladium-catalyzed alkene difunctionalization reaction has been investigated. Kinetic analysis provides evidence of turnover-limiting attack of a proposed quinone methide intermediate with MeOH and suggests that copper is involved in productive product formation, not just catalyst turnover. Through examination of substrate electronic effects, a Jaffé relationship was observed correlating rate to electronic perturbation at two positions of the substrate. Ligand effects were evaluated to provide evidence of rapid ligand exchange between palladium and copper as well as a correlation between ligand electronic nature and enantioselectivity.

Figure 1

Stereochemical model for diastereoselectivity.

Figure 2

Typical reaction profiles as measured by O₂ uptake. A. Full O₂ uptake profile. B. Equilibration time. C. Pseudo-zero order reaction profile. D. Pseudo-first order reaction profile.

Figure 3

First order dependence on [Pd]. Conditions: [substrate] = 0.16 M, [Cu] = 0.0017 M [KHCO₃] = 0.026 M, 1:4 MeOH:toluene, O₂, 25 °C.

Figure 4

Saturation in [substrate] and [Cu]. Conditions: [Pd] = 0.0026 M, [KHCO₃] = 0.026 M, 1:4 MeOH:toluene, O₂, 25 °C, A. [Cu] = 0.0053 M, B. [Cu] = 0.0017 M, C. [substrate] = 0.16 M, D. [substrate] = 0.026 M

Figure 5

Formation of substrate-copper complex. Does not account for observed independent saturation in [substrate] and [Cu].

Figure 6

Zero order dependence on partial pressure of O₂ (with N₂), conditions: [Pd] = 0.0026 M, [Cu] = 0.0017 M, [substrate] = 0.16 M, [KHCO₃] = 0.026 M, 1:4 MeOH:toluene, 25 °C, total pressure = 850 torr.

Figure 7

Dependence of rate and yield on [KHCO₃], conditions: [Pd] = 0.0026 M, [Cu] = 0.0017 M, [substrate] = 0.16 M, 1:4 MeOH:toluene, O₂, 25 °C.

Figure 8

Positive dependence on [MeOH], conditions: [Pd] = 0.0026 M, [Cu] = 0.0017 M, [substrate] = 0.16 M, [KHCO₃] = 0.010 M, O₂, 25 °C.

Figure 9

Evaluation of substrate electronic effect on rate. Hammett plots: log(k_X/k_H) vs. σ_p (A) and σ_m (B).

Figure 10

Jaffé plots show a linear free energy relationship between substrate electronics and reaction rate. ρ_p and ρ_m values from each plot are within error.

Figure 11

Quinone methide resonance structures.

Figure 12

Hammett plot of log(er) vs. σ showing ligand electronic effect on enantioselectivity.

Figure 13

Working stereochemical model.

Scheme 1

Pd-catalyzed difunctionalization of alkenes with an adjacent ortho-phenol and tethered nucleophile.

Scheme 2

Initial discovery of Pd-catalyzed alkene dialkoxylation and evidence for a quinone methide intermediate.

Scheme 3

Evidence for attack of palladium-bound quinone methide intermediate.

Scheme 4

Proposed mechanisms to account for potential role of copper.

Scheme 5

Evidence for initial oxypalladation at the β-position.