Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers with Isotopically-Labeled Grignard Reagents

Abstract

In this manuscript we highlight the potential of stereospecific nickel-catalyzed cross-coupling reactions for applications in the pharmaceutical industry. Using an inexpensive and sustainable nickel catalyst, we report a gram-scale Kumada cross-coupling reaction. Reactions are highly stereospecific and proceed with inversion at the benzylic position. We also expand the scope of our reaction to incorporate isotopically labeled substituents.

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

“…With nickel complexes 3 – 5 in hand, we examined them as catalysts in a cross‐coupling reaction of a benzylic ether. We chose cross‐coupling of tetrahydropyran 6 with methylmagnesium iodide, a prototypical stereospecific Kumada‐type coupling reaction that is robust, high‐yielding, and scales well (Figure a) . The active catalyst is proposed to be either Ni 0 or Ni I species ligated by the bidentate phosphine ligand; under typical reaction conditions the precatalyst would undergo reduction and oxidation pathways in situ to generate the active catalyst.…”

Asymmetric synthesisviastereospecific C–N and C–O bond activation of alkyl amine and alcohol derivatives

“…In subsequent publications, Jarvo and coworkers used this traceless directing group for stereospecific, nickel-catalyzed cross-coupling reactions of secondary benzylic ethers with aryl Grignard reagents to afford enantioenriched triarylmethanes. 38,64 Additionally, they utilized a similar directing group for the stereospecific, nickel-catalyzed Negishi cross-coupling of secondary benzylic esters with dimethylzinc. 40…”

Stereospecific Cross‐Coupling Reactions Provide Conformationally‐Biased Arylalkanes with Anti‐Leukemia Activity

“…[10,11,12] In 2014, our laboratory reported an C sp 3 À C sp 3 Kumada cross-coupling reaction of aryl tetrahydropyrans (THPs) and tetrahydrofurans (Scheme 1a). [13,14,15] This ring-opening reac-tion utilizes an achiral nickel catalyst to couple a benzylic ether with Grignard reagents in a stereospecific manner. Importantly, the THP starting material is generated in a single step from the commercially available aldehyde by a diastereoselective Prins cyclization.…”

“…In 2014, our laboratory reported an C sp 3 −C sp 3 Kumada cross‐coupling reaction of aryl tetrahydropyrans (THPs) and tetrahydrofurans (Scheme a) . This ring‐opening reaction utilizes an achiral nickel catalyst to couple a benzylic ether with Grignard reagents in a stereospecific manner.…”