Energetics of Dynamic Kinetic Asymmetric Transformation in Suzuki–Miyaura Coupling

Abstract

The enantioselective cross-coupling reactions that transform a racemic mixture into an enantio-enriched product are in high contemporary demand. Elucidation of mechanism involving catalytic enantioselective transformation with racemic substrates is often challenging. Herein, we provide mechanistic insights derived through a comprehensive density functional theory (B3LYP-D3) investigation, on the origin of stereoinduction in a Rh-catalyzed asymmetric allylic arylation of racemic 3-chlorocyclohex-1-ene by using arylboronic acid. Energetically most preferred pathway is found to proceed through (a) a transmetalation wherein aryl group gets transferred from the boron of arylboronic acid to the Rh center of the catalyst, (b) an oxidative addition (OA) of Rh to the C–Cl bond of cyclohexenyl chloride, and (c) a reductive elimination (RE) leading to the bond formation between the Rh-bound phenyl and cyclohexenyl moiety to furnish the final arylated product. We note that each enantiomer of the substrate follows different OA modes, which is highly suggestive of a dynamic kinetic asymmetric transformation (DYKAT). Although the likelihood of DYKAT has been routinely invoked in the literature, quantitative energetic details, as well as mechanistic underpinnings such as the identity of the common intermediate, generally remain scarce. The R enantiomer of cyclohexenyl chloride is found to undergo an anti-SN2′ OA, whereas the S enantiomer prefers an anti-SN2 route to the common prochiral η3-Rh-π-allyl intermediate. High enantioselectivity in the ensuing RE, favoring the S enantiomer of the product, is traced to the lower activation barrier, which, in turn, arises from the lower distortion energy in the RE transition state when the si face of Rh-bound cyclohexenyl forms the bond with the phenyl group than when the re face is involved. The mechanistic insights presented herein are expected to be valuable toward understanding the DYKAT mechanism of conversion of racemic substrates to an enantiopure product.

The Catalytic Formation of Atropisomers and Stereocenters via Asymmetric Suzuki–Miyaura Couplings

“…Recent mechanistic studies have been conducted by the groups of Fletcher and Sunoj . As per their studies, the reaction involves a dynamic-kinetic asymmetric transformation (DYKAT), allowing the access to a single enantiomer starting from a racemic substrate.…”

“…109 Recent mechanistic studies have been conducted by the groups of Fletcher 110 and Sunoj. 111 As per their studies, the reaction involves a dynamic-kinetic asymmetric transformation (DYKAT), allowing the access to a single enantiomer starting from a racemic substrate. First, the Rh(I) undergoes transmetalation, followed by solvent coordination and oxidative addition of the allyl chloride to generate a Rh-allyl intermediate, which upon reductive elimination, delivers the enantioenriched product.…”

Unexpected alkyl isomerization at the silicon ligand of an unsaturated Rh complex: combined experiment and theory

“…Often, the mechanisms of catalysis of Rh dimer complexes implicate the formation of 14-electron monomers. 10,11 Some examples include the hydroformylation of terminal alkenes with formaldehyde; 12 the carbonylative coupling of iodobenzenes with furfural; 13 the enantioselective Suzuki-Miyaura cross-coupling of racemic substrates; 14 and the coupling of terminal alkynes with carboxylic acids, 15,16 amongst others.…”