Unveiling the Reactivity of Part Per Million Levels of Cobalt-Salen Complexes in Hydrosilylation of Ketones.

A series of air-stable cobalt(III)salen complexes Co-1 to Co-4 have been synthesized and employed in the hydrosilylation of ketones. Notably, the most intricately tailored Co-3 pre-catalyst exhibited exceptional catalytic activity under mild reaction conditions. The developed catalytic hydrosilylation protocol proceeded with an unusual ppm level (5 ppm) catalyst loading of Co-3 and achieved a maximum turnover number (TON) of 200,000. A wide variety of aromatic, aliphatic, and heterocyclic ketones encompassing both electron-donating and electron-withdrawing substituents were successfully transformed into the desired silyl ethers or secondary alcohols in moderate to excellent yields.

Reduction-Specified Coupling Reactions of Nitroarenes by Heterogeneous Cobalt Catalysis.

The in-depth study on reduction-specified coupling reactions of the nitroarenes by heterogeneous cobalt catalysis opens a door for diversified syntheses of functional N-containing molecules. Guided by the structure-function relationship of heterogeneous materials, rational design of nano-catalysts can effectively regulate the routes of organic reactions. Precise transformation of the intermediates generated during the nitroarene reduction with a suitable nano-catalyst is a promising way to develop new tandem reactions, and to synthesize structurally novel compounds that are of difficult access with the conventional approaches.

Transfer Hydrogenation of Vinyl Arenes and Aryl Acetylenes with Ammonia Borane Catalyzed by Schiff Base Cobalt(II) Complexes.

A series of bench-stable Co(II) complexes containing hydrazone Schiff base ligands were evaluated in terms of their activity and selectivity in carbon-carbon multiple bond transfer hydrogenation. These cobalt complexes, especially a Co(II) precatalyst bearing pyridine-2-yl-N(Me)N=C-(1-methyl)imidazole-2-yl ligand, activated by LiHBEt3, were successfully used in the transfer hydrogenation of substituted styrenes and phenylacetylenes with ammonia borane as a hydrogen source. Key advantages of the reported catalytic system include mild reaction conditions, high selectivity and tolerance to functional groups of substrates.

Cobalt-Catalyzed Electroreductive Alkylation of Unactivated Alkyl Chlorides with Conjugated Olefins.

Reactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt-catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes. Co-catalyzed activation of alkyl chlorides is performed under electroreductive conditions, and the resulting reactions constitute formal alkyl-alkyl bond formation. In addition to developing an operationally simple methodology, detailed mechanistic studies provide insights into the elementary steps of a proposed catalytic cycle. In particular, we propose a switch in the mechanism of C-Cl bond activation from nucleophilic substitution to halogen atom abstraction, which is critical for efficiently generating alkyl radicals. These mechanistic insights were leveraged in designing ligands that enable couplings of primary, secondary, and tertiary alkyl chlorides.

Dual-Catalysed Intermolecular Reductive Coupling of Dienes and Ketones.

We report a mild, catalytic method for the intermolecular reductive coupling of feedstock dienes and styrenes with ketones. Our conditions allow concomitant formation of a cobalt hydride species and single-electron reduction of ketones. Subsequent selective hydrogen-atom transfer from the cobalt hydride generates an allylic radical which can selectively couple with the persistent radical-anion of the ketone. This radical-radical coupling negates unfavourable steric interactions of ionic pathways and avoids the unstable alkoxy radical of previous radical olefin-carbonyl couplings, which were limited, as a result, to aldehydes. Applications of this novel and straightforward approach include the efficient synthesis of drug molecules, key intermediates in drug synthesis and site-selective late-stage functionalisation.

Dual-Catalytic Structural Isomerisation as a Route to α-Arylated Ketones.

Isomerisation reactions provide streamlined routes to organic compounds which are otherwise hard to directly synthesise. The most common forms are positional, geometrical or stereochemical isomerisations which involve the relocation of a double bond or a change in relative location of groups in space. In contrast, far fewer examples of structural (or constitutional) isomerisation exist where the connectivity between atoms is altered. The development of platforms capable of such rearrangement poses a unique set of challenges because chemical bonds must be selectively cleaved, and new ones formed without overall addition or removal of atoms. Here, we show that a dual catalytic system can enable the structural isomerisation of readily available allylic alcohols into more challenging-to-synthesise α-arylated ketones via a H-atom transfer initiated semi-pinacol rearrangement. Key to our strategy is the combination of a cobalt catalyst and photocatalyst under reductive, protic conditions which allows intermediates to propagate catalytic turnover. By providing an unusual disconnection to structural motifs which are difficult to access through direct arylation, we anticipate inspiring other advanced catalytic isomerisation strategies that will further retrosynthetic logic for complex molecule synthesis.

Enantioselective Synthesis of α-Aryl Ketones by a Cobalt-Catalyzed Semipinacol Rearrangement.

A highly enantioselective cobalt-catalyzed semipinacol rearrangement of symmetric α,α-diarylallylic alcohols is disclosed. A chiral cobalt-salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical-polar crossover steps. This methodology provides access to enantioenriched α-aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2-aryl migration. A combination of readily available reagents, silane and N-fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para- and meta-halogenated, mildly electron-rich and electron-poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron-rich aryl rings whereas very electron-deficient and ortho-substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron-rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Electrohydrogenation of Nitriles with Amines by Cobalt Catalysis.

Catalytic hydrogenation of nitriles represents an efficient and sustainable one-step synthesis of valuable bulk and fine chemicals. We report herein a molecular cobalt electrocatalyst for selective hydrogenative coupling of nitriles with amines using protons as the hydrogen source. The key to success for this reductive reaction is the use of an electrocatalytic approach for efficient cobalt-hydride generation through a sequence of cathodic reduction and protonation. As only electrons (e- ) and protons (H+ ) as the redox equivalent and hydrogen source, this general electrohydrogenation protocol is showcased by highly selective and straightforward synthesis of various functionalized and structurally diverse amines, as well as deuterium isotope labeling applications. Mechanistic studies reveal that the electrogenerated cobalt-hydride transfer to nitrile process is the rate-determining step.

Hydrogen Source Tuned Regiodivergent Asymmetric Hydroalkylations of 2-Substituted 1,3-Dienes with Aldehydes by Cobalt-Catalysis.

Catalytic methods allowing for the reliable prediction and control of diverse regioselectivity along with the control of enantioselectivity to access different regio- and enantiomers by switching the least reaction parameters are one of the most attractive ways in organic synthesis, which provide access to diverse enantioenriched architectures from identical starting materials. Herein, a Co-catalyzed regiodivergent and enantioselective reductive hydroalkylation of 1,3-dienes with aldehydes has been achieved, furnishing different enantioenriched homoallylic alcohol architectures in good levels of enantioselectivity. The reaction features the switch of regioselectivity tuned by the selection of proton source. The use of an acid as proton source provided asymmetric 1,2-hydroalkylation products under reductive conditions, yet asymmetric 4,3-hydroalkylation products were obtained with silane as hydride source. This catalytic protocol allows for the access of homoallylic alcohols with two continuous saturated carbon centers in good levels of regio-, diastereo-, and enantioselectivity.

Asymmetric Synthesis of Chiral Calix[4]arenes with Both Inherent and Axial Chirality via Cobalt-Catalyzed Enantioselective Intermolecular C-H Annulation.

Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt-catalyzed C-H activation/annulation strategy in high yield with excellent enantio- and diastereoselectivity (up to > 99% ee and > 20:1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio- and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.

Cobaltaelectro-Catalyzed C-H Activation for Central and Axial Double Enantio-Induction.

In recent years, enantioselective electrocatalysis has surfaced as an increasingly-effective platform for sustainable molecular synthesis. Despite indisputable progress, strategies that allow the control of two distinct stereogenic elements with high selectivity remain elusive. In contrast, we, herein, describe electrochemical cobalt-catalyzed C-H activations that enable the installation of chiral stereogenic centers along with a chiral axis with high levels of enantio- and diastereoselectivities. The developed electrocatalysis strategy allowed for C-H/N-H activations/annulations with cyclic and non-cyclic alkenes providing expedient access to various central as well as atropo-chiral dihydroisoquinolinones paired to the valuable hydrogen evolution reaction. Studies on the atropo-stability of the obtained compounds demonstrated that the exceedingly mild conditions ensured by the electrocatalytic process were key for the achieved high stereoselectivities.

Cobalt-Catalyzed Enantio- and Regioselective C(sp3 )-H Alkenylation of Thioamides.

An enantioselective cobalt-catalyzed C(sp3 )-H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

Dual Photochemical H-Atom Transfer and Cobalt Catalysis for the Desaturative Synthesis of Phenols from Cyclohexanones.

Phenols are integral aromatic molecules widely encountered in the structure of natural products and routinely utilised for the synthesis of high-value materials. Accessing highly substituted derivatives can often be difficult, especially when their functionalization pattern does not match the intrinsic reactivity leveraged by electrophilic aromatic substitution (SE Ar) chemistry. Here, we provide an alternative and mechanistically distinct approach for phenol synthesis using saturated cyclohexanone precursors. This process operates at ambient temperature, under simple purple light irradiation, and features a dual catalytic manifold carrying four sequential H-atom transfer processes.

Cobalt-Catalyzed Regiodivergent Ring-Opening Dihydroboration of Arylidenecyclopropanes to Access Skipped Diboronates.

Ligand-controlled regiodivergent cobalt-catalyzed ring-opening dihydroboration of arylidenecyclopropanes is developed to access synthetically versatile skipped diboronates with catalysts generated in situ from Co(acac)2 and dpephos or xantphos. A variety of arylidenecyclopropanes reacted with pinacolborane (HBpin) to form the corresponding 1,3- or 1,4-diboronates in high isolated yields and with high regioselectivity. Skipped diboronate products from these reactions can undergo various transformations to allow selective installation of two different functional groups along alkyl chains. Mechanistic studies suggest that these reactions combine cobalt-catalyzed ring-opening hydroboration of arylidenecyclopropanes and hydroboration of homoallylic or allylic boronate intermediates.

Cobalt-Catalyzed Wagner-Meerwein Rearrangements with Concomitant Nucleophilic Hydrofluorination.

We report a cobalt-catalyzed Wagner-Meerwein rearrangement of gem-disubstituted allylarenes that generates fluoroalkane products with isolated yields up to 84 %. Modification of the counteranion of the N-fluoropyridinium oxidant suggests the substrates undergo nucleophilic fluorination during the reaction. Subjecting the substrates to other known metal-mediated hydrofluorination procedures did not lead to observable 1,2-aryl migration. Thus, indicating the unique ability of these cobalt-catalyzed conditions to generate a sufficiently reactive electrophilic intermediate capable of promoting this Wagner-Meerwein rearrangement.

Cobalt-Catalyzed Asymmetric Deuteration of α-Amidoacrylates for Stereoselective Synthesis of α,ß-Dideuterated α-Amino Acids.

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,ß-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l-DOPA.

Experimental and Computational Studies on Cobalt(I)-Catalyzed Regioselective Allylic Alkylation Reactions.

Here, we report the development of cobalt(I)-catalyzed regioselective allylic alkylation reactions of tertiary allyl carbonates with 1,3-dicarbonyl compounds. A family of well-defined tetrahedral cobalt(I) complexes bearing commercially available bidentate bis(phosphine) ligands [(P,P)Co(PPh3 )Cl] are synthesized and explored as catalysts in allylic alkylation reactions. The catalyst [(dppp)Co(PPh3 )Cl] (dppp=1,3-Bis(diphenylphosphino)propane) enables the alkylation of a large variety of tertiary allyl carbonates with high yields and excellent regioselectivity for the branched product. Remarkably, this methodology is selective for the activation of tertiary allyl carbonates even in the presence of secondary allyl carbonates. This contrasts with the selectivity observed in cobalt-catalyzed allylic alkylations enabled by visible light photocatalysis. Mechanistic insights by means of experimental and computational investigations support a Co(I)/Co(III) catalytic cycle.

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.

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(Oi 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.

Cobalt-Catalyzed Enantioselective Hydroamination of Arylalkenes with Secondary Amines.

Catalytic asymmetric hydroamination of alkenes with Lewis basic amines is of great interest but remains a challenge in synthetic chemistry. Here, we developed a Co-catalyzed asymmetric hydroamination of arylalkenes directly using commercially accessible secondary amines. This process enables the efficient access to valuable α-chiral tertiary amines in good to excellent yields and enantioselectivities. Mechanistic studies suggest that the reaction includes a CoH-mediated hydrogen atom transfer (MHAT) with arylalkenes, followed by a pivotal catalyst controlled SN 2-like pathway between in situ generated electrophilic cationic alkylcobalt(IV) species and free amines. This radical-polar crossover strategy not only provides a straightforward and alternative approach for the synthesis of enantioenriched α-tertiary amines, but also underpins the substantial opportunities in developing asymmetric radical functionalization of alkenes with various free nucleophiles in oxidative MHAT catalysis.

Ligand-Controlled Stereoselective Synthesis of 2-Deoxy-ß-C-glycosides by Cobalt Catalysis.

2-Deoxy-ß-C-glycosides represent an important class of carbohydrates that are present in many bioactive molecules. However, owing to the lack of substituents at the C2 position, the stereoselective synthesis of 2-deoxy-ß-C-glycosides is highly challenging. Herein, we report a ligand-controlled stereoselective C-alkyl glycosylation reaction to access 2-deoxy-ß-C-alkyl glycosides from readily available glycals and alkyl halides. This method exhibits broad substrate scope and excellent diastereoselectivity under very mild conditions. In addition, unprecedented stereodivergent synthesis of 2-deoxy-C-ribofuranosides is achieved using different chiral bisoxazoline ligands. Mechanistic studies suggest that hydrometallation of the glycal with the bisoxazoline-ligated Co-H species may be the turnover-limiting and stereodetermining step of this transformation.