A Unified Explanation for Chemoselectivity and Stereospecificity of Ni-Catalyzed Kumada and Cross-Electrophile Coupling Reactions of Benzylic Ethers: A Combined Computational and Experimental Study

Abstract

Ni-catalyzed C(sp 3)-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetallation with the Grignard reagent and syn reductive elimination produces the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic CO bond cleavage and transmetallation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular S N 2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp 3)-O bond activation.

Identification of the Active Catalyst for Nickel‐Catalyzed Stereospecific Kumada Coupling Reactions of Ethers

“…However, when cod is present, low‐valent complexes can be stabilized by forming off‐cycle resting state 3 ; this resting state is observed by absorption spectroscopy (Figure d–e). These conclusions are consistent with the results of our prior investigations of the mechanism of nickel‐catalyzed coupling of benzylic ethers, including DFT calculations of the reaction coordinate diagram for the catalytic cycle …”

Mechanisms of Nickel-Catalyzed Cross-Coupling Reactions

“…The stereospecific couplings of benzylic and allylic ethers and esters [40,41] give access to allylic diarylmethanes and arylmethanes with biological activity, such as analogs to the antibreast-cancer drug tamoxifen [42]. With NHC or bisphosphine ligands, oxidative addition occurs via an S N 2 pathway, where nucleophilic attack of Ni to the benzyl ether results in inversion at the benzylic position ( Figure 2C) [43]. The following sequence of transmetalation and concerted reductive elimination leads to overall inversion of the stereochemistry at the benzylic position.…”

16-Electron Nickel(0)-Olefin Complexes in Low-Temperature C(sp2)–C(sp3) Kumada Cross-Couplings

“…Notably, the vast majority of the reported catalytic systems to forge such C–C bonds rely on the use of highly electron donating ligands: namely, phosphines, diamines, diimines and NHCs (Figure B) . It is generally accepted that the success of these ligands hinges on providing the metal center with an adequate electronic demand to aid in the oxidative addition and reductive elimination steps. ,, In addition to taming the rates of oxidative addition and reductive elimination, the formation of L–Ni after reductive elimination prevents the metal center from decomposing and being eliminated from the system as Ni black.…”