Nickel‐Catalyzed Enantioconvergent Borylation of Racemic Secondary Benzylic Electrophiles

Abstract

Nickel‐catalyzed cross‐coupling has emerged as the most versatile approach to date for achieving enantioconvergent carbon–carbon bond formation using racemic alkyl halides as electrophiles. In contrast, there have not yet been reports of the application of chiral nickel catalysts to the corresponding reactions with heteroatom nucleophiles to produce carbon–heteroatom bonds with good enantioselectivity. Herein, we establish that a chiral nickel/pybox catalyst can borylate racemic secondary benzylic chlorides to provide enantioenriched benzylic boronic esters, a highly useful family of compounds in organic synthesis. The method displays good functional group compatibility (e.g., being unimpeded by the presence of an indole, a ketone, a tertiary amine, or an unactivated alkyl bromide), and both of the catalyst components (NiCl2⋅glyme and the pybox ligand) are commercially available.

The Persistent Radical Effect in Organic Synthesis

“…[216] Note that the development of new (enantio)selective CÀCc oupling protocols is an active and timely research field. [217] Along with CÀCb ond formations,N icatalyzed radical borylation [218] and silylation [219] reactions of alkyl halides have been developed.…”

Copper(I)‐Catalyzed Enantioconvergent Borylation of Racemic Benzyl Chlorides Enabled by Quadrant‐by‐Quadrant Structure Modification of Chiral Bisphosphine Ligands

“…[4][5][6][7] Mechanistic studies on such copper(I)-catalyzed borylation reactions have led to ap lausible catalytic cycle that involves ar adical intermediate.Recently,our group has also reported acopper-(I)-catalyzed borylative radical cyclization by exploiting the reactivity of such radicals (Scheme 1b). [10][11][12][13] Tr ansition-metal-catalyzed enantioselective reactions involving radical mechanisms are considered challenging molecular transformations relative to conventional nonradical reactions.I nt ypical transition-metal-mediated reactions,t he chiral environment provided by the chiral catalyst leads to enantioselective recognition of the substrate through strong intermolecular interactions,a st he metal center firmly binds the substrate.H owever,t he interaction between chiral catalysts and neutral radical species is typically weak because of the rather long distance between them, even in the stereoselectivity-determining transition state. [9] Therefore,i th as been anticipated that the enantioselective borylation of achiral radical intermediates by chiral copper(I) catalysts should provide optically active alkylboronates from the corresponding racemic alkyl chlorides (Scheme 1c).…”

“…[9] Therefore,i th as been anticipated that the enantioselective borylation of achiral radical intermediates by chiral copper(I) catalysts should provide optically active alkylboronates from the corresponding racemic alkyl chlorides (Scheme 1c). [10][11][12][13] Tr ansition-metal-catalyzed enantioselective reactions involving radical mechanisms are considered challenging molecular transformations relative to conventional nonradical reactions.I nt ypical transition-metal-mediated reactions,t he chiral environment provided by the chiral catalyst leads to enantioselective recognition of the substrate through strong intermolecular interactions,a st he metal center firmly binds the substrate.H owever,t he interaction between chiral catalysts and neutral radical species is typically weak because of the rather long distance between them, even in the stereoselectivity-determining transition state. [9,14] Thus,a n effective catalyst-design strategy to achieve high enantioselectivity in radical-mediated reactions is highly desirable.W e envisioned that design flexibility of the chiral catalyst would be crucial to finding the optimal catalyst able to offer control over unexpected transition states,s uch as those in radicalmediated reactions (Scheme 1c).…”

Copper(I)‐Catalyzed Enantioconvergent Borylation of Racemic Benzyl Chlorides Enabled by Quadrant‐by‐Quadrant Structure Modification of Chiral Bisphosphine Ligands

“…In addition, molecular transformations via achiral radical intermediates with chiral catalysts convergently furnish optically active products from racemic starting materials . Therefore, it has been anticipated that the enantioselective borylation of achiral radical intermediates by chiral copper(I) catalysts should provide optically active alkylboronates from the corresponding racemic alkyl chlorides (Scheme c) …”