Mechanism and Origin of Enantioselectivity in Nickel-Catalyzed Alkyl–Alkyl Suzuki Coupling Reaction

Enantioselective Suzuki coupling reactions are a widely used method in asymmetric synthesis of chiral compounds. In an important extension of this protocol, 1-bromo-1-fluoroalkanes were coupled with alkyl-9-BBN using chiral NiCl₂L* as the catalyst (where L* = bis­(pyrrolidine) ligand) under Suzuki conditions to obtain a product with a stereogenic center bearing a fluorine. In view of the current interest in chiral fluorine-containing compounds as well as lack of clarity on the mechanism of Ni-catalyzed asymmetric Suzuki coupling reactions, we decided to examine various mechanistic pathways of the title reaction. The (U)­M06 density functional theory computations have been employed to identify the energetically preferred pathway first and then to probe the origin of high enantioselectivity. In particular, we have compared the likely involvement of different redox couples such as Ni(0)/Ni­(II) and Ni­(I)/Ni­(III) in the catalytic cycle. For the Ni(0)/Ni­(II) pathway, both singlet and triplet spin states have been considered whereas a doublet spin multiplicity has been examined in the case of the Ni­(I)/Ni­(III) system. The most preferred catalytic pathway is found to proceed through a Ni­(I)/Ni­(III) redox cycle with key mechanistic steps such as (a) a transmetalation involving the transfer of the alkyl group of 9-BBN to the Ni-catalyst, (b) an oxidative addition of bromo­(fluoro) alkane to give a penta-coordinate Ni­(III) intermediate, and (c) an enantio-controlling reductive elimination (RE) that facilitates the C–C bond formation between the Ni-bound fluoroalkyl and alkyl moieties to yield the final product. The transmetalation is found to be the turnover determining transition state (TS) according to the activation span model. The RE is found to be the enantio-controlling step, wherein the TS for the addition of the si prochiral face of the Ni-bound fluoro alkyl moiety to the alkyl group is 4.3 kcal/mol lower than the corresponding re face addition. Distortion-Interaction analysis suggested that the extent of distortion in the catalyst Ni­(Br)L* fragment in the si face reductive elimination TS is much lower than in the re face addition, thus making a vital contribution to the energy difference between diastereomeric TS.