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Evaluation of the relative rates of the cobalt‐catalyzed C(sp2)–C(sp3) Suzuki–Miyaura cross‐coupling between the neopentylglycol ester of 4‐fluorophenylboronic acid and N‐Boc‐4‐bromopiperidine established that smaller N‐alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air‐stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross‐coupling of an indole‐5‐boronic ester nucleophile with a piperidine‐4‐bromide electrophile that is relevant to the synthesis of reported toll‐like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe⋅B(OiPr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. A first‐order dependence on the cobalt precatalyst and a saturation regime in nucleophile were observed, supporting turnover‐limiting transmetalation and the origin of the observed trends in N‐imine substitution. [ABSTRACT FROM AUTHOR]

Homoenolates are unique synthetic intermediates which display umpolung reactivity. Homoenolates and homoenolate equivalents like cyclopropanols have seen a recent surge in popularity due to their particular utility for accessing β‐functionalized carbonyl derivatives. This popularity has been enabled by the development of protocols for facile access to cyclopropanols and homoenolates from a variety of readily available starting materials. This microreview will highlight common strategies for generating cyclopropanols and metal homoenolates, as well as procedures for homoenolate functionalization, with a particular emphasis on protocols that have appeared after 2003. As an amphoteric molecule, two main reactivity modes have been established: the homoenolate reacts as a carbon nucleophile for β‐functionalization reactions and/or as a carbonyl electrophile, a strategy which has only emerged in the past few years. This microreview will highlight the use of homoenolates as convenient intermediates for accessing especially challenging motifs. The use of homoenolate chemistry in the context of natural product and pharmaceutical synthesis will also be presented. This microreview highlights recent strategies for the synthesis of homoenolates and cyclopropanols, as well as protocols for homoenolate functionalization, both as nucleophilic and electrophilic reagents. The unique reactivity and synthetic utility of metal homoenolates is further showcased in recent examples of their use in natural product and pharmaceutical synthesis. [ABSTRACT FROM AUTHOR]

Since their discovery, metal homoenolates have been widely explored as carbon-based nucleophiles for the ß-functionalization of carbonyl derivatives. Only recently has it been reported that metal homoenolates can react as carbonyl electrophiles. In this context, we have recently discovered that cyclopropylamines can be prepared from cyclopropanols via zinc homoenolate intermediates. This Synpacts article will present an overview of the reactivity of homoenolates and our strategy to employ these intermediates for the synthesis of cyclopropylamines. Key mechanistic observations and their influence on reaction optimization will also be discussed. 1 Introduction 2 Homoenolates as Nucleophiles--Selected Reactivity 3 Homoenolates as Electrophilic Reagents 4 Conclusion [ABSTRACT FROM AUTHOR]

The Cover Feature shows a metal homoenolate intermediate in equilibrium between its ring‐opened and ring‐closed tautomeric forms. The ring‐opened form allows the homoenolate intermediate to be harnessed for bond‐forming reactions – either as a nucleophile at the carbon–metal bond or as an electrophile at the carbonyl. The balance between a reactive ring‐opened intermediate and a latent ring‐closed intermediate is reminiscent of the open (reactive) and closed forms of the venus fly trap found in nature, whose forms are depicted in the image also. More information can be found in the Microreview by S. A. L. Rousseaux et al. [ABSTRACT FROM AUTHOR]

Phenoxyimine (FI)-nickel(II)(2-tolyl)(DMAP) compounds were synthesized and evaluated as precatalysts for the C(sp 2 )-C(sp 3 ) Suzuki-Miyaura cross coupling of (hetero)arylboronic acids with alkyl bromides. With 5 mol % of the optimal (Me OMe FI)Ni(Aryl)(DMAP) precatalyst, the scope of the cross-coupling reaction was established and included a variety of (hetero)arylboronic acids and alkyl bromides (>50 examples, 33-97% yield). A β-hydride elimination-reductive elimination sequence from reaction with potassium isopropoxide base, yielding a potassium (FI)nickel(0)ate, was identified as a catalyst activation pathway that is responsible for halogen atom abstraction from the alkyl bromide. A combination of NMR and EPR spectroscopies identified (FI)nickel(II)-aryl complexes as the resting state during catalysis with no evidence for long-lived organic radical or odd-electron nickel intermediates. These data establish that the radical chain is short-lived and undergoes facile termination and also support a "recovering radical chain" process whereby the (FI)nickel(II)-aryl compound continually (re)initiates the radical chain. Kinetic studies established that the rate of C(sp 2 )-C(sp 3 ) product formation was proportional to the concentration of the (FI)nickel(II)-aryl resting state that captures the alkyl radical for chain propagation. The proposed mechanism involves two key and concurrently operating catalytic cycles; the first involving a nickel(I/II/III) radical propagation cycle consisting of radical capture at (FI)nickel(II)-aryl, C(sp 2 )-C(sp 3 ) reductive elimination, bromine atom abstraction from C(sp 3 )-Br, and transmetalation; and the second involving an off-cycle catalyst recovery process by slow (FI)nickel(II)-aryl → (FI)nickel(0)ate conversion for nickel(I) regeneration.

Evaluation of the relative rates of the cobalt-catalyzed C(sp 2 )-C(sp 3 ) Suzuki-Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4-bromopiperidine established that smaller N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py) 3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe⋅B(O i Pr) 3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. A first-order dependence on the cobalt precatalyst and a saturation regime in nucleophile were observed, supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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.

Cobalt(II) halides in combination with phenoxy-imine (FI) ligands generated efficient precatalysts in situ for the C(sp 2 )-C(sp 3 ) Suzuki-Miyaura cross coupling between alkyl bromides and neopentylglycol (hetero)arylboronic esters. The protocol enabled efficient C-C bond formation with a host of nucleophiles and electrophiles (36 examples, 34-95%) with precatalyst loadings of 5 mol%. Studies with alkyl halide electrophiles that function as radical clocks support the intermediacy of alkyl radicals during the course of the catalytic reaction. The improved performance of the FI-cobalt catalyst was correlated with decreased lifetimes of cage-escaped radicals as compared to diamine-type ligands. Studies of the phenoxy(imine)-cobalt coordination chemistry validate the L,X interaction leading to the discovery of an optimal, well defined, air-stable mono-FI cobalt(II) precatalyst structure.

The ability to understand and predict reactivity is essential for the development of new reactions. In the context of Ni-catalyzed C(sp 3 )-O functionalization, we have developed a unique strategy employing activated cyclopropanols to aid the design and optimization of a redox-active leaving group for C(sp 3 )-O arylation. In this chemistry, the cyclopropane ring acts as a reporter of leaving-group reactivity, since the ring-opened product is obtained under polar (2e) conditions, and the ring-closed product is obtained under radical (1e) conditions. Mechanistic studies demonstrate that the optimal leaving group is redox-active and are consistent with a Ni(I)/Ni(III) catalytic cycle. The optimized reaction conditions are also used to synthesize a number of arylcyclopropanes, which are valuable pharmaceutical motifs.