A new nickel-catalyzed reaction could give chemists a faster and more selective way to transform one of organic chemistry’s most stubborn starting materials: internal alkenes. In a study published in CCS Chemistry, researchers from the Shanghai Institute of Organic Chemistry at the Chinese Academy of Sciences and the National University of Singapore report an enantioselective reductive Heck reaction and Heck coupling that converts internal, or “inner,” alkenes into valuable chiral products. The method uses aryl or alkenyl trifluoromethanesulfonates as coupling partners and a carefully designed nitrogen-heterocyclic carbene, or NHC, ligand bound to nickel. Under relatively mild conditions, the catalyst forms carbon–carbon bonds with high regioselectivity and enantioselectivity, producing molecules that contain three-dimensional structures important in medicinal chemistry and natural-product synthesis.
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
