A collaborative research team led by Shi-Liang Shi at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and Ming Joo Koh's group at the National University of Singapore, reported an enantioselective reduction of Heck and Heck coupling reactions of inner alkenes catalyzed by a nitrogen-heterocyclic carbene (NHC)-nickel complex. This method, using aryl trifluoromethanesulfonate as an electrophile, achieved highly regioselective and enantioselective functionalization of inner alkenes, constructing a diverse range of chiral arylized products. The reaction conditions were mild, and the functional group compatibility was excellent. By using sterically hindered and tunably flexible NHC ligands, side reactions were effectively suppressed, and precise stereocontrol was achieved. This strategy provides a universal platform for the asymmetric functionalization of inner alkenes and demonstrates its potential application in the late-stage modification of drug-related molecules. The article was published as an open access Research Article in CCS Chemistry , the flagship journal of the Chinese Chemical Society.
Background information:
Transition metal-catalyzed asymmetric carbon functionalization reactions of olefins are a highly efficient strategy for constructing chiral carbons, widely applied in medicinal chemistry, natural product synthesis, and materials science. Among the many methods, asymmetric Heck -type reactions (including reductive Heck and conventional Heck reactions) have attracted considerable attention due to their ability to rapidly construct chiral carbon skeletons. The key step in these reactions is the selective carbon metallization of olefins, which can simultaneously introduce carbon groups and metal species, generating chiral alkyl metal intermediates.
Despite significant progress in intramolecular asymmetric Heck reactions, intermolecular versions, particularly those targeting inner-olefin substrates, remain challenging. The inherent steric hindrance of inner-olefins reduces their affinity for metal catalysts, hindering the migration insertion process; simultaneously, the lack of electroinductive properties of their substituents often leads to the formation of mixtures of Markovnikov and anti-Markovnikov isomers. Furthermore, inner-olefins are prone to isomerization, and alkyl metal intermediates readily undergo β-H elimination, further increasing the difficulty of the reaction. Existing strategies have achieved the functionalization of inner-olefins with the assistance of directing groups, but the installation and removal of these directing groups increase the number of synthetic steps. Therefore, developing a universal asymmetric Heck -type reaction for inner-olefins that does not require directing groups is of great importance.
In recent years, the team led by Shi-Liang Shi at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, has been dedicated to developing sterically hindered and tunably flexible NHC ligands, achieving a series of advancements in nickel-catalyzed asymmetric Heck-type coupling of alkenes. Based on this, the team envisioned addressing a long-standing challenge in internal olefin reactions by rationally designing NHC ligands and reaction conditions. Specifically, sterically hindered NHC ligands can suppress β-H elimination from alkyl metal intermediates, flexible frameworks facilitate the migration and insertion of hindered alkenes, and deep chiral cavities provide excellent enantioselectivity control. Recently, the team reported an NHC-nickel-catalyzed enantioselective reduction of Heck and Heck coupling reactions of internal alkenes. This method uses aryl or alkenyl trifluoromethanesulfonate esters as electrophiles, achieving efficient coupling with various internal alkenes (including cyclic, acyclic, and bridged-cyclic alkenes), and constructing chiral dihydrofuran, dihydropyrrole, chromated, and thiochromated structural units in one step. This strategy requires no directing group, operates under mild conditions, and exhibits excellent regioselectivity, enantioselectivity, and functional group compatibility.
Highlights of this article :
Optimization of Reaction Conditions: Using 2,5-dihydrofuran and aryltrifluoromethanesulfonate as model substrates, the authors optimized the nickel-catalyzed asymmetric reduction Heck coupling reaction of inner alkenes. Through systematic screening of a series of NHC ligands, it was found that sterically hindered NHC ligands with 3,5-dimethylphenyl substituents efficiently promoted the reaction, yielding β-arylated chiral dihydrofuran products with excellent yields and enantioselectivity. Solvent screening showed that i PrOH was crucial for improving yield, chemoselectivity, and enantioselectivity. Notably, the asymmetric Heck reaction of 2,5-dihydrofuran has not been previously reported, mainly due to the difficulty in regio and stereocontrol caused by its isomerization problem.
The reduction of Heck's substrates is well-compatible with a wide range of aryl trifluoromethanesulfonates, including substrates containing electron-donating or electron-withdrawing groups (aniline, ether, fluorine, ester, acetal), as well as substrates containing drug-related heterocycles such as morpholine, benzofuran, and dibenzofuran. All yield the target product (3a–3o) with high yield and enantioselectivity (88–94% ee). Alkenyl electrophilic reagents are also applicable, yielding trisubstituted olefin products (3n). The endogenous olefin substrate range covers N -Boc, N -Cbz, N -PMP protected dihydropyrroles, various substituted styrene groups (containing ether, fluorine, chlorine, OTBS, etc.), as well as thiochromated, chromated, non-cyclic, and bridged intracyclic olefins (4a–4q). All yield the product with good to excellent yields and regioselectivity and enantioselectivity (up to 94% ee). Gram-scale experiments (8.0 mmol) yielded the target product with 95% yield and 90% ee, demonstrating the practicality of the method.
Heck Reaction Substrate Scope: The β-selective asymmetric Heck reaction was further explored. Using LiO t Bu as a base and t BuOH as a solvent, the sterically hindered NHC ligand L4 achieved Heck coupling of 2,5-dihydrofuran with aryl trifluoromethanesulfonate, yielding the β arylated product in 92% yield and 94% ee. This reaction is applicable to ortho-, meta-, and para-substituted aryl trifluoromethanesulfonates, and substrates containing aniline, ether, fluorine, chlorine, ester, acetal, and methylthio groups can be efficiently transformed (5a–5z) with good to excellent yields and enantioselectivity up to 96% ee. Heterocyclic substrates (5x–5z) and alkenyl electrophiles (5aa) also reacted smoothly. This method provides a convenient route for the synthesis of β-arylated chiral dihydrofurans.
Reaction Mechanism: Control experiments showed that aryl trifluoromethanesulfonate was crucial for the initiation of the catalytic cycle; deuteration experiments showed that the hydrogen source came from the methine of i PrOH or i PrONa, rather than the traditional nickel-hydrogen initiation pathway, ruling out the nickel-hydrogen insertion mechanism; radical capture experiments did not inhibit the reaction, indicating a non-radical pathway; kinetic studies showed that the reaction was zero-order with respect to the olefin and aryl trifluoromethanesulfonate, and first-order with respect to the catalyst. Based on this, the authors proposed the following catalytic cycle: (1) Oxidative addition of aryl trifluoromethanesulfonate to Ni(0) catalyst to generate aryl nickel (II) intermediate I; (2) Regioselective and enantioselective carbon metallization of the inner olefin to generate alkyl nickel species I; (3) In the absence of iPrON , β-H elimination dominated, yielding the Heck product; (4) In the presence of i PrONa , hydrogen transfer and reductive elimination occurred, releasing the product and regenerating the catalyst. The sterically hindered NHC ligand played a key role in inhibiting β-H elimination, promoting migration insertion, and providing a chiral environment.
Summary and Outlook:
In summary, the authors developed an NHC-nickel-catalyzed enantioselective reduction of Heck and Heck coupling reactions of inner alkenes. Using aryl/alkenyl trifluoromethanesulfonate esters as electrophiles, this method achieved high regioselectivity and enantioselective arylation of inner alkenes under mild conditions, constructing diverse chiral dihydrofuran, dihydropyrrole, chromanthate, and thiochromanthate skeletons. This method requires no directing group, exhibits excellent functional group compatibility, and high stereoselectivity, providing a practical platform for the asymmetric functionalization of inner alkenes. The sterically hindered and tunably flexible NHC ligand is key to achieving high reactivity and selectivity.
This work was recently published in CCS Chemistry , with Hai-Yu Wu from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences as the first author, and Shi-Liang Shi, Ming Joo Koh, and Zi-Chao Wang as corresponding authors.
---
About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem .
About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/ .
CCS Chemistry
10.31635/ccschem.026.202607864
Experimental study
Not applicable
Enantioselective Reductive Heck and Heck Coupling of Internal Cyclic Alkenes Enabled by Nickel/N-Heterocyclic Carbene Catalysis
10-Jul-2026
There is no conflict of interest to report.