Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates

Abstract

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst's structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications.

Figure 1

A) Reaction conditions for NLE experiments. B) No NLE in the product ee. C) NLE in the P:H ratio. P:H ratios were determined via ¹H NMR analysis of the crude reaction mixture. D) Two possible scenarios explaining the observed NLE in the P:H ratio.

Figure 2

Dependence of the P:H ratio on the Pd:2b ratio. P:H ratios were determined via ¹H NMR analysis of the crude reaction mixture.

Figure 3

Catalytic cycle

Figure 4

A) CAPT catalysts used in the present study. B) Multivariate model for the P:H ratios obtained with PAs 2a–2l in the 1,1-diarylation of benzyl acrylate 5a. The P:H ratios expressed in kcal/mol are reported in parentheses.

Figure 5

Dependence of the ee on the benzyl substituent. Enantiomeric excesses determined by SFC analysis as an average of two experiments.

Figure 6

Graphical trend analysis of the stereoselectivities obtained from the combination of 7 PAs and 13 benzyl acrylates.

Figure 7

A) Model and parameters for 17 benzyl acrylates (5a–5c, 5e–5r) and PA 2a. 5d is an outlier for this model. B) Model and parameters for 12 PAs (2a–2l) and benzyl acrylate 5a. C) Low-lying energy TSs TS-R and TS-S. Substrate 5a is highlighted in green. All the energy values are reported in kcal/mol. Method A: M06-2X/SDD:6–311++G(d,p)[PCM-Et₂O]. Method B: M06-2X/SDD:6–311++G(d,p). Method C: ωB97XD/SDD:6–311++G(d,p). Exp: experimental values obtained from equation ΔΔG^‡ = −RTln(e.r.).

Figure 8

Multivariate model for 11 PAs (2b–2l) and 18 acrylates (5a–5r). The model includes 119 datapoints divided in a training set (78 points, black circles) and a validation set (41 points, red squares). The validation set presented one outlier (blue triangle).

Scheme 1

A) 1,1-diarylation of benzyl acrylates using CAPT and Pd catalysis. B) Hypothesized reaction mechanism involving a CAPT strategy for the 1,1-difuntionalization of olefins.

Scheme 2

A) Deuterium-labeling experiment. B) Effect of β-HE selectivity on stereoselectivity. C) Crossover experiments.