Mechanism, Reactivity, and Selectivity in Palladium-Catalyzed Redox-Relay Heck Arylations of Alkenyl Alcohols

Abstract

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of β-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG‡ of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C–O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay effeciency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.

Palladium-Catalyzed Enantioselective Heck Alkenylation of Acyclic Alkenols Using a Redox-Relay Strategy

“…This result is consistent with computational analysis wherein the polarization of the alkene in the transition state is stabilized by remote C–O dipole interactions. 12 Therefore, we anticipated that site selective migratory insertion could be adequately addressed using this substrate class. Another problem we suspected to be of greater significance is that of site selective β-hydride elimination from an intermediate like B .…”

Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene

“…The transition structure TS2 for the migratory insertion step leading to the 4,1-addition precursor INT6 has a free energy of activation of ΔG‡ of 6.6 kcal/mol and INT6 is accessed with a ΔG = −13.8 kcal/mol. If the exchange of isoprene and DMF is in analogy to earlier studies, 16 rapid, then the Curtin-Hammett principle would be applicable. The barriers of the migratory insertion step are 5.6 kcal/mol and 8.1 kcal/mol for the 1,x-addition pathway and the 4,1-addition pathway, respectively.…”

“…16 Following alkene migratory insertion, σ-π isomerization results in the formation of the π-allyl stabilized Pd-intermediate 4 . Base (OH − ) promoted isomerization promoted by hydroxide formed through decomposition of sodium carbonate and coordination of the alkenyl boronic acid generates Pd-complex 6 .…”

Mechanism of the palladium-catalyzed hydrothiolation of alkynes to thioethers: a DFT study

“…The 6-31G basis set with polarization (d and p) [50] was employed with all of the atoms except palladium, for which the Stuttgart-Dresden effective core potential (SDD) [51] was utilized for relativistic effects and to reduce the number of electrons in the research systems. The SDD basis set has been applied successfully to many of the mechanistic studies of transition-metal-catalyzed reaction systems [52][53][54]. Vibrational analysis was applied at the same level to determine the character in which the transition state has an imaginary frequency and the stationary structure has no imaginary frequency.…”