Mechanistic Investigations of Phenoxyimine–Cobalt(II)-Catalyzed C(sp²)–C(sp³) Suzuki–Miyaura Cross-Coupling

Abstract

The mechanism of phenoxyimine (FI)−cobalt-catalyzed C(sp 2 )−C(sp 3 ) Suzuki−Miyaura cross-coupling was studied using a combination of kinetic measurements and catalytic and stoichiometric experiments. A series of dimeric (FI)cobalt(II) bromide complexes, [(4-CF 3 PhFI)CoBr] 2 , [(4-OMePhFI)CoBr] 2 , and [(2,6-di i PrPhFI)CoBr] 2 , were isolated and characterized by 1 H and 19 F NMR spectroscopies, solution and solid-state magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, X-ray crystallography, and diffusion-ordered NMR spectroscopy (DOSY). One complex, [(4-CF 3 PhFI)CoBr] 2 , was explored as a single-component precatalyst for C(sp 2 )−C(sp 3 ) Suzuki−Miyaura cross-coupling. Addition of potassium methoxide to [(4-CF 3 PhFI)CoBr] 2 generated the corresponding (FI)cobalt(II) methoxide complex as determined by 1 H and 19 F NMR and EPR spectroscopies. These spectroscopic signatures were used to identify this compound as the resting state during catalytic C(sp 2 )− C(sp 3 ) coupling. Variable time normalization analysis (VTNA) of in situ catalytic 19 F NMR spectroscopic data was used to establish an experimental rate law that was first-order in a (FI)cobalt(II) precatalyst, zeroth-order in the alkyl halide, and first-order in an activated potassium methoxide−aryl boronate complex. These findings are consistent with turnover-limiting transmetalation that occurs prior to activation of the alkyl bromide electrophile. The involvement of boronate intermediates in transmetalation was corroborated by Hammett studies of electronically differentiated aryl boronic esters. Together, a cobalt(II)/cobalt(III) catalytic cycle was proposed that proceeds through a "boronate"-type mechanism.

Phenoxythiazoline (FTz)‐Cobalt(II) Precatalysts Enable C(sp2)–C(sp3) Bond‐Formation for Key Intermediates in the Synthesis of Toll‐like Receptor 7/8 Antagonists**

“…1). These experiments were informed by mechanistic studies of (4‐CF 3 ‐Ph‐FI)cobalt(II)‐catalyzed C(sp 2 )–C(sp 3 ) Suzuki–Miyaura cross‐coupling, which support a “transmetalation‐first” mechanism involving the reaction of activated aryl boronate and (FI)cobalt(II) methoxide in the turnover‐limiting step [37] . Consistent with these data, a first‐order dependence on (H‐FTz)CoBr(py) 3 ( 5 a ) and a zeroth‐order dependence on alkyl bromide ( 2 a ) were obtained.…”

“…The reaction was also zeroth‐order in base‐borate complex KOMe⋅B(O i Pr) 3 , consistent with no catalyst inhibition by this reagent and highlighting a role of trialkylborates in attenuating the basicity of otherwise strong alkoxides. Previously, excess KOMe was shown to react with (FI)cobalt(II) bromide compounds to form the catalytically inactive alkoxide aggregate [KCo(OMe) 3 ] n and free K(FI) ligand [37] . Notably, the reaction also exhibited no apparent dependence on the concentration of boronic ester 1 b and is likely due to the low solubility of the activated aryl boronate ( 9 ) involved in transmetalation, which is at saturation in 2 : 1 MeCN/THF.…”

“…Previously, excess KOMe was shown to react with (FI)cobalt(II) bromide compounds to form the catalytically inactive alkoxide aggregate [KCo(OMe) 3 ] n and free K(FI) ligand. [37] Notably, the reaction also exhibited no apparent dependence on the concentration of boronic ester 1 b and is likely due to the low solubility of the activated aryl boronate (9) involved in transmetalation, which is at saturation in 2 : 1 MeCN/THF. Addition of more arylboronic ester (1 b) to the reaction mixture did not increase the amount of soluble aryl boronate (9) that participates in turnover-limiting transmetalation and a change in rate was not observed.…”

Phenoxythiazoline (FTz)‐Cobalt(II) Precatalysts Enable C(sp2)–C(sp3) Bond‐Formation for Key Intermediates in the Synthesis of Toll‐like Receptor 7/8 Antagonists**

“…Phenoxyimine (FI) cobalt complexes have proven particularly effective, and comprehensive mechanistic studies support a Co(II)-Co(III) cycle with alkyl radical intermediates derived from the electrophile (Scheme 2). [35][36][37] Here we describe kinetic and mechanistic studies that demonstrate increased rates of CÀ C bond formation with smaller N-imine substituents of the FI ligand, a consequence of accelerated rates of transmetalation. These insights led to the rational design of air-stable phenoxythiazoline (FTz)cobalt(II) precatalysts for C(sp 2 )-C(sp 3 ) Suzuki-Miyaura cross-coupling relevant to the synthesis of intermediates for TLR7/8 antagonists (Scheme 2).…”

A General Copper Catalytic System for Suzuki–Miyaura Cross-Coupling of Unactivated Secondary and Primary Alkyl Halides with Arylborons

“…The Nakamura, Byers, , and Chirik groups independently disclosed that the well-defined iron complexes could catalyze Suzuki–Miyaura reactions of alkyl halides with arylborates or arylborons. Cobalt catalysis was recently realized for the transformation with L,X-type ligands . Notwithstanding these advances, the majority of precedents are limited by functionality tolerance and strict reaction conditions (inert atmosphere).…”