Internal alkenes are common in complex organic molecules, but they are considerably more difficult to functionalize than terminal alkenes. Their substituents crowd the carbon–carbon double bond, making it harder for a metal catalyst to approach and insert into the alkene. At the same time, the two alkene carbons often offer similar electronic environments, so the catalyst may generate mixtures of regioisomers rather than a single defined product. Internal alkenes can also migrate along a carbon chain through isomerization, while the alkyl–metal intermediates formed during catalysis may undergo β-hydride elimination. These competing pathways can destroy both efficiency and stereochemical control. Although directing groups have previously helped guide metal catalysts toward internal alkenes, those groups must usually be installed and later removed, adding extra steps to a synthesis.

The new strategy addresses these challenges through the combined design of the nickel catalyst, the NHC ligand and the reaction medium. The NHC ligands used by the researchers are sterically demanding but structurally flexible. Their bulky substituents help shield the reactive nickel center and suppress unwanted β-hydride elimination, while their flexible framework allows the catalyst to accommodate crowded internal alkenes during migratory insertion. The ligand also creates a chiral pocket around the metal. As the alkene enters this environment, one of its two possible orientations is favored over the other, allowing the reaction to generate predominantly one enantiomer of the product. This control is essential because enantiomers can have dramatically different biological properties, even though they share the same molecular formula and connectivity.

The team first optimized the reaction using 2,5-dihydrofuran, a cyclic internal alkene, and an aryl trifluoromethanesulfonate. Screening a series of NHC ligands revealed that structures bearing bulky 3,5-dimethylphenyl groups were particularly effective. The optimized system delivered β-arylated chiral dihydrofuran products in high yield and with strong enantiomeric enrichment. Solvent selection proved to be unusually important. Isopropanol, or iPrOH, improved not only the chemical yield but also chemoselectivity and enantioselectivity. The result is notable because asymmetric Heck chemistry involving 2,5-dihydrofuran has been difficult to achieve, in part because this substrate can isomerize and because the catalyst must control both the position and the three-dimensional outcome of aryl addition.

The reductive Heck coupling displayed a broad electrophile scope. Aryl trifluoromethanesulfonates containing electron-donating or electron-withdrawing substituents underwent the transformation efficiently. The compatible groups included aniline, ether, fluorine, ester and acetal functionalities, as well as drug-related heterocycles such as morpholine, benzofuran and dibenzofuran. The resulting products were generally obtained with high yields and enantiomeric excesses ranging from 88% to 94%. Alkenyl trifluoromethanesulfonates could also participate, allowing the preparation of trisubstituted alkenes. This range is important for pharmaceutical chemistry, where late-stage coupling methods must tolerate many functional groups without requiring extensive protection or deprotection strategies.

The alkene component was similarly versatile. In addition to 2,5-dihydrofuran, the reaction accepted N-Boc-, N-Cbz- and N-PMP-protected dihydropyrroles, substituted styrene-derived internal alkenes and sulfur- or oxygen-containing cyclic systems. Functional groups such as ethers, fluorine, chlorine and silyl-protected alcohols remained intact during the reaction. Thiochromene-, chromene-, acyclic and bridged cyclic alkenes could also be transformed, with the best examples reaching approximately 94% enantiomeric excess. In one gram-scale experiment using 8.0 millimoles of substrate, the desired product was isolated in 95% yield and 90% enantiomeric excess. Such a result suggests that the chemistry is not limited to small exploratory reactions and may be adaptable to the preparation of useful quantities of chiral intermediates.

The researchers also examined the conventional asymmetric Heck pathway, in which the alkyl–nickel intermediate undergoes β-hydride elimination to form an alkene rather than receiving a hydrogen atom. Using lithium tert-butoxide as the base and tert-butanol as the solvent, the sterically hindered NHC ligand enabled the coupling of 2,5-dihydrofuran with an aryl trifluoromethanesulfonate to produce a β-arylated product in 92% yield and 94% enantiomeric excess. The reaction accommodated ortho-, meta- and para-substituted aryl partners, as well as compounds bearing aniline, ether, fluorine, chlorine, ester, acetal and methylthio groups. Heterocyclic and alkenyl electrophiles also reacted successfully, providing a direct route to β-arylated chiral dihydrofurans.

Mechanistic experiments indicate that the reaction does not follow the most familiar nickel-hydride pathway. Deuterium-labeling studies showed that the hydrogen incorporated into reductive Heck products originates from the methine group of isopropanol or from isopropoxide, rather than from a preformed nickel–hydrogen species. Control experiments established that the aryl trifluoromethanesulfonate is necessary to initiate catalysis, while radical-trapping tests did not suppress the reaction, arguing against a free-radical mechanism. Kinetic measurements found the process to be zero-order in both the alkene and the aryl electrophile but first-order in catalyst concentration, suggesting that catalyst activation or a catalyst-centered step influences the overall rate.

On the basis of these observations, the authors propose a catalytic cycle beginning with oxidative addition of the aryl trifluoromethanesulfonate to a Ni(0)–NHC complex, generating an aryl–nickel(II) intermediate. The internal alkene then inserts into the nickel–carbon bond in a regioselective and enantioselective fashion, forming a chiral alkyl–nickel species. If isopropoxide is absent, β-hydride elimination dominates and produces the Heck-coupled alkene. When isopropoxide is present, hydrogen transfer and reductive elimination instead release the reduced arylated product and regenerate the active catalyst. The bulky, flexible NHC ligand is central to this balance: it discourages unproductive β-hydride elimination when reduction is desired, promotes insertion of sterically hindered alkenes and maintains a chiral environment throughout the bond-forming steps.

By combining broad functional-group tolerance with control over both regioselectivity and enantioselectivity, the nickel/NHC system offers a potentially general platform for modifying internal alkenes without directing groups. The products include chiral dihydrofurans, dihydropyrroles, chromene-related structures and thiochromene-related structures, many of which resemble frameworks found in biologically active compounds. The study also demonstrates how ligand architecture can solve several problems at once: steric protection of the metal center, selective alkene insertion, suppression of side reactions and asymmetric induction. Published as an open-access research article in CCS Chemistry, the work could attract attention well beyond catalytic methodology because it provides a practical way to add complexity to molecules late in a synthesis—one of the most sought-after capabilities in modern drug discovery and chemical manufacturing.

Subject of Research: Asymmetric functionalization of internal cyclic alkenes using nickel/N-heterocyclic carbene catalysis.

Article Title: Enantioselective Reductive Heck and Heck Coupling of Internal Cyclic Alkenes Enabled by Nickel/N-Heterocyclic Carbene Catalysis

News Publication Date: 10-Jul-2026

Web References: CCS Chemistry, https://doi.org/10.31635/ccschem.026.202607864

References: Wu, Hai-Yu, et al. “Enantioselective Reductive Heck and Heck Coupling of Internal Cyclic Alkenes Enabled by Nickel/N-Heterocyclic Carbene Catalysis.” CCS Chemistry. DOI: 10.31635/ccschem.026.202607864

Image Credits: CCS Chemistry

Keywords

Nickel catalysis, N-heterocyclic carbene, asymmetric synthesis, reductive Heck reaction, Heck coupling, internal alkenes, enantioselective catalysis, chiral molecules, organic chemistry, drug discovery

Organic molecules endowed with multiple stereocentres underpin the complexity and functionality of countless biologically active compounds, including natural products and pharmaceuticals. Historically, the stereocontrolled formation of carbon–carbon (C–C) bonds, particularly C(sp³)–C(sp³) linkages adjacent to one another—termed vicinal stereocentres—has posed substantial synthetic challenges. This difficulty escalates as the steric demands of the substituents increase, notably in scenarios where quaternary carbon stereocentres are involved. These fully substituted carbons are prevalent in natural products, conferring rigidity and unique biological properties but complicating their synthetic accessibility.

A salient strategy in contemporary organic synthesis involves transforming racemic alkyl halides into chiral products with high enantiopurity. Conventional approaches often require pre-formed organometallic reagents or stoichiometric chiral auxiliaries, which can be sensitive, expensive, and lack broad functional group tolerance. The recently disclosed methodology circumvents these limitations by exploiting cobalt catalysis to mediate a reductive radical process, capturing racemic alkyl halides and guiding their addition to imines with exquisite control over stereochemistry.

The core of this innovation lies in the enantioconvergent nature of the reaction. Enantioconvergency ensures that both enantiomers of the racemic starting material are transformed into a single enantiomer of the product, maximizing efficiency and reducing waste. This contrasts with simple kinetic resolution, where only one enantiomer is selectively converted. Through nuanced mechanistic control, the cobalt catalyst orchestrates selective radical formation and addition under mild reductive conditions, thus enabling the construction of contiguous stereogenic centers with high diastereo- and enantioselectivity.

A critical aspect of the methodology is its competency to forge diverse vicinal stereogenic motifs, spanning tertiary–tertiary, tertiary–quaternary, and even quaternary–quaternary carbon centres. This versatility is transformative, considering the synthetic challenges inherent in forming quaternary-quaternary vicinal stereocentres due to steric hindrance and the propensity for side reactions. The reported process thus expands the toolkit available to chemists for assembling complex, stereochemically rich molecules that can serve as key intermediates or active agents in drug discovery and material science.

Unlike many radical-based processes, which can be indiscriminate or require harsh conditions, this cobalt-catalysed reaction operates under relatively mild reductive environments. This gentleness broadens the reaction’s compatibility with various sensitive functional groups, a valuable asset in complex molecule synthesis. Functional groups that often thwart radical or organometallic transformations, such as alcohols, esters, and heteroatoms, are well-tolerated in this protocol, emphasizing its utility in late-stage functionalization of complex molecules.

The procedure’s substrate scope is equally impressive. Starting from readily available racemic alkyl halides, the approach extends to an array of imines, permitting access to important chiral frameworks including amino acids, organophosphorus compounds, amino alcohols, and γ-lactams. These structural motifs are ubiquitous in pharmaceuticals and natural products, signifying the practical and broad-reaching impact of this methodology. The ability to install adjacent stereocentres enantioselectively in such diverse contexts is a leap forward in synthetic strategy.

Moreover, the methodology beckons new opportunities in the stereoselective construction of C-glycosyl amino acids—a class of compounds where a sugar unit is carbon-linked to an amino acid backbone. C-glycosyl amino acids exhibit enhanced metabolic stability compared to their O-linked counterparts, rendering them attractive in medicinal chemistry. The cobalt-catalysed radical addition strategy paves a streamlined synthetic avenue to these entities, facilitating exploration into novel bioactive compounds and peptide mimetics.

Mechanistic elucidation reveals that the cobalt catalyst initiates a reductive activation of racemic alkyl halide substrates via single-electron transfer, generating alkyl radicals. These radicals undergo enantioselective addition to chiral imine intermediates, formed in situ or pre-prepared, followed by judicious protonation and catalyst regeneration steps. The controlled radical pathway mitigates undesired side reactions such as homocoupling or reduction, maintaining high selectivity and yield, which underscores sophisticated catalyst design and reaction optimization.

The implications of this research extend beyond synthetic methodology into industrial synthesis and medicinal chemistry domains. The ability to engineer vicinal stereocentres effectively facilitates access to drug candidates with enhanced metabolic properties and pharmacological profiles, given that stereochemistry profoundly influences biological activity. Furthermore, the scalability and functional group tolerance of this method could accelerate the synthesis of complex molecules, reducing the steps and cost associated with traditional multi-stage enantioselective protocols.

In addition to synthetic versatility, this cobalt-mediated system highlights the resurgence of earth-abundant transition metal catalysts in asymmetric synthesis. Cobalt, being more abundant and less toxic compared to traditionally employed noble metals like palladium and rhodium, offers a sustainable alternative. The catalytic system’s performance encourages re-examining cobalt catalysts for other challenging transformations, promoting greener and economically favorable practices in chemical manufacturing.

Anticipating future directions, researchers might explore expanding the substrate scope further to include more complex polyfunctionalized alkyl halides or different classes of electrophilic partners beyond imines. Integration with other catalytic systems or tandem reactions might afford even more complex molecular architectures in a single operationally simple process. Such expansions could synthesize natural product analogues or facilitate late-stage diversification of lead compounds.

The reported advances also suggest potential in asymmetric radical-mediated polymerization or material science applications, where precise stereochemical control can dictate material properties. By harnessing cobalt catalysis to control radical intermediates with high stereocontrol, new chiral polymers or functional materials exhibiting unique mechanical or electronic features may become accessible.

This research exemplifies the power of combining radical chemistry with asymmetric catalysis to overcome synthetic challenges that have persisted despite decades of traditional development. The strategic design marrying enantioconvergent catalysis with radical processes ushers in a paradigm where racemic starting materials—once considered problematic in enantioselective synthesis—are transformed with predictability and precision into highly valuable stereochemically complex products.

In summary, the cobalt-catalysed enantioconvergent reductive radical addition of racemic alkyl halides to imines represents a landmark development in asymmetric organic synthesis. Its capacity to deliver contiguous stereocentres, including those challenging quaternary points, under mild and broadly compatible conditions portends wide applicability in synthetic design. This methodology not only advances fundamental chemistry but also fuels progress in drug development, materials science, and sustainable catalytic technologies. As this conceptual and practical framework gains traction, it promises to inspire further exploration of radical enantioselective processes catalysed by earth-abundant metals.

Subject of Research:
Development of cobalt-catalysed enantioconvergent radical addition reactions for the construction of vicinal stereogenic carbon centres from racemic alkyl halides.

Article Title:
Enantioconvergent radical addition of racemic alkyl halides to access vicinal stereocentres.

Article References:
Wu, X., Xia, T., Bai, J. et al. Enantioconvergent radical addition of racemic alkyl halides to access vicinal stereocentres. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01967-w

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