Nickel-catalyzed regio- and enantioselective borylalkynylation of inactive alkenes based on C–H⋯π interactions

Professor Chao Wang's team at Tianjin Normal University recently reported a non-covalent C–H⋯π interaction-based olefin functionalization strategy, achieving highly regio- and enantioselective1,2-borylalkynylation reactions of unactivated alkenes. Utilizing the weak interaction between the aryl side arm of the chiral diamine ligand andthe π-donor group of the olefin substrate, they successfully achieved precise three-component coupling of the olefin, B₂pin₂, and alkynyl bromide under nickel catalysis. The study achieved efficient construction of remote chiral centers by controlling the transition state of migration insertion through non-covalent interactions. This strategy eliminates the dependence on traditional covalently directed groups, complementing existing covalently directed models and opening up new avenues for site- and stereoselective bifunctionalization of unactivated alkenes. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:

Unactivated alkenes, as a class of inexpensive and readily available basic chemical raw materials, are widely found in petrochemical products and biomass-derived molecules, serving as key synthetic building blocks for constructing complex chiral molecules. Therefore, developing efficient and highly selective bifunctionalization methods for unactivated alkenes is not only a core challenge in the development of modern synthetic chemistry methodology but also provides a strategic pathway for the rapid construction of functional molecular libraries. Existing strategies mainly rely on pre-installed covalently directed groups on the substrate, whose application is limited by the substrate structure and involves additional installation and removal steps. Especially for alkenes containing linear π- donor groups such as cyano and alkynyl groups, traditional covalently directed strategies are difficult to apply because they cannot form stable cyclic metal intermediates. Non-covalent interactions are widespread in nature and have been widely applied in asymmetric hydrogenation and CH functionalization. However, to date, no universal strategy has been established in the field of olefin functionalization that can stabilize transition states and simultaneously control regioselectivity and stereoselectivity. Because these interactions have low bond energies and non-fixed spatial orientations, ensuring effective locking of these more flexible transition state conformations is challenging. Therefore, developing a non-activated olefin regio-enantioselective bifunctionalization reaction based on non-covalent interactions and with strong universality has become a cutting-edge challenge in this field.

Highlights of this article:

To address the aforementioned challenges, this study innovatively developed a nickel-catalyzed regio- and enantioselective borylalkynylation reaction of inactive alkenes based on C–H⋯π interactions. This strategy precisely controls the configuration of alkyl metal intermediates in the nickel-catalyzed system through directional C–H⋯π interactions between a designed chiral diamine ligand and π- donor groups (such as cyano, alkynyl, and aryl groups) in the alkene substrate, achieving for the first time highly regio- and enantioselective 1,2-borylalkynylation of inactive alkenes. This reaction system exhibits excellent compatibility with various functional groups, yielding single regioisomers with good to excellent yields and high enantioselectivity for electron-donating and electron-withdrawing substituted aryl alkynyl bromides, as well as heteroaryl rings and multi-level alkyl alkynyl bromides (Figure 2). Furthermore, the alkene substrate range is broad, encompassing allylic nitriles, homoallylic nitriles, aryl alkenes, and even non-conjugated alynynes; the bifunctional reagents can also be extended to different borate esters. Notably, this strategy has been successfully applied to the late-stage modification of various drug molecule derivatives, achieving gram-scale synthesis and diverse derivatization transformations, demonstrating its practical potential in the precise synthesis of complex chiral molecules (Figure 3). This work provides a novel and universal strategy for the regio- and stereoselective bifunctionalization of inactive alkenes, which has significant application value in the synthesis of functional molecules and chiral drugs.

In the mechanistic study, this research, through a combination of systematic experimental verification and theoretical calculations, elucidates the crucial role of non-covalent C–H⋯π interactions in controlling the reaction regio and enantioselectivity. As shown in Figure 4, controlled experiments demonstrate that octene substrates lacking π-donor groups generate a mixture of various regioisomers, while the enantioselectivity is significantly reduced when gaseous propylene participates in the reaction, confirming the importance of specific interactions between π-donor groups and ligands. Ligand structure modification experiments further show that when the ligand side arms lack benzylic C–H bonds (e.g., L15, L16) or the side arm length is extended (L18), both reactivity and enantioselectivity decrease significantly, indicating that the geometric specificity of C–H⋯π interactions is crucial. Furthermore, ligand kinetic isotope experiments using the deuterated ligand L13-D observed a reverse kinetic isotope effect, strongly supporting the participation of C–H bonds in the rate-determining step in the transition state stabilization process of non-covalent interactions. DFT calculations further reveal the origin of stereoselectivity at the energy and structural levels. Calculations show that the migration insertion step is both the rate-determining and enantioselectivity-determining step of the reaction. In the dominant transition state, a clear C–H⋯π interaction exists between the ligand benzylic C–H bond and the substrate cyano group, resulting in a 2.1 kcal/mol lower energy for the (R)-configuration transition state compared to the (S)-configuration, thus achieving enantioselectivity control. These results collectively demonstrate that the spatial orientation of metal intermediates can be effectively controlled through precisely designed weak interactions between ligands and substrates, providing a new solution for achieving regio- and stereoselective bifunctionalization of unactivated alkenes.

Summary and Outlook:

In summary, we have developed a novel strategy for the regio- and enantioselective functionalization of inactive alkenes using non-covalent C–H⋯π interactions. By employing a chiral diamine ligand capable of recognizing π-donor groups such as nitrile, alkynyl, and aryl groups, this method enables precise control of regio- and enantioselectivity in the 1,2-borylalkynylation of inactive alkenes. Mechanistic studies, including experimental and computational investigations, reveal the crucial role of C–H⋯π interactions in stabilizing transition states and guiding stereoselectivity. This mild and modular approach allows for the construction of long-range chiral centers on a range of inactive alkenes, including substrates challenging conventional coordination strategies. The resulting products possess orthogonal synthetic handles suitable for further modification, highlighting the broad synthetic applicability of this method. We anticipate that this work will expand the scope of asymmetric catalysis and inspire future developments in the field of non-covalent interaction-driven olefin functionalization.

The above work was published as a Research Article in CCS Chemistry. Rui He (Master's) , Aichen Li (Master's) , and Xinjie Dong (Master's) are the co-first authors of the article, and Professor Chao Wang  of Tianjin Normal University is the corresponding author.

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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/.