Computational Investigation of Selectivity in Suzuki–Miyaura Coupling of Secondary Alkyl Boranes

Abstract

The Suzuki–Miyaura cross-coupling reaction is an important route to forming carbon–carbon bonds. Suzuki coupling of secondary alkyls containing β-hydrogens is challenging, due in part to a competing and undesired β-hydride elimination. We perform density functional electronic structure calculations on model compounds to study the selectivity of Suzuki coupling of secondary alkyl boranes. Results indicate that the rate and selectivity of the desired reductive elimination are strongly influenced by how the reactants and ligand interact with a coordinatively unsaturated PdII intermediate. Agostic interactions between PdII and reactant β-hydrogens provide facile routes to β-hydride elimination, while coordination of electron-donating reactant groups to PdII slows the reductive elimination. The bulky ligands used in typical Suzuki couplings, such as the SPhos dialkylbiarylphosphine, appear to block both types of undesired interaction while stabilizing the reductive elimination transition state.

Stereospecific Cross-Coupling of Secondary Organotrifluoroborates: Potassium 1-(Benzyloxy)alkyltrifluoroborates

“…Calculations have revealed that the hydrogens on the most substituted carbon undergo β-hydride elimination most readily. 22 Upon coordination of the stabilizing carbonyl group, the alkyl chain is rotated in such a way that the β-hydrogens at the most substituted carbons are no longer able to become co-planar, thus preventing β-hydride elimination. 14 Finally, electron-withdrawing groups in the substrate have also been found to inhibit β-hydride elimination.…”

“…The carbonyl of the amide withdraws electron density from the hydrogens β to the palladium, disfavoring β-hydrogen agostic interactions with the metal, thereby further inhibiting β-hydride elimination. 22 …”

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…65,66,67,68,69 Furthermore, in all cases racemic alkyl electrophiles were employed, yet the products are produced in high enantiomeric excess. Recent mechanistic studies have elucidated the operating catalytic cycle (Scheme 6).…”

At the Forefront of the Suzuki–Miyaura Reaction: Advances in Stereoselective Cross-Couplings

“…Prior research has demonstrated that these types of ligands can serve several roles in the prevention of β-hydride elimination. One important advantage is their ability to reduce the necessary agostic interactions between the metal and the neighbouring β-hydrogens [78] in two ways: (1) by acting as an inductively electron withdrawing group, thus reducing the electron density of the β-hydrogens, and (2) by coordinating to the metal centre, which reduces the electron deficiency of the metal. Coordination to the metal centre also has the added benefit of potentially inhibiting syn-β-hydride elimination by restricting the conformation of the organometallic intermediate.…”