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Transition-Metal-Catalyzed C―H Bond Functionalization of Amines via Transient Directing Group Strategies

Ying Kang , Zhuoqi Li , Shiming Fan , Shouxin Liu

Progress in Chemistry ›› 2026, Vol. 38 ›› Issue (5) : 870 -887.

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Progress in Chemistry ›› 2026, Vol. 38 ›› Issue (5) : 870-887 DOI: 10.7536/PC20250811
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Transition-Metal-Catalyzed C―H Bond Functionalization of Amines via Transient Directing Group Strategies
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Abstract

Amines serve as crucial structural units in pharmaceuticals， functional materials， and natural products， and their efficient synthesis has always been a core topic in organic chemistry research. In recent years， transition-metal-catalyzed C―H bond activation has emerged as a highly efficient strategy for constructing complex amine derivatives. The core challenge in amine C―H bond functionalization lies in directing the transition metal to selectively cleave the target C―H bond. Direct use of the native amine group as directing groups often leads to catalyst deactivation and side reactions such as β-hydride elimination. While covalently linked directing auxiliaries enable precise activation， they require additional installation and removal steps， reducing synthetic efficiency. The recently developed transient directing group （TDG） strategies achieves selective activation of C―H bonds through reversible binding between the directing group and the substrate. This approach not only allows precise targeting of the desired C―H bond but also eliminates the need for pre-installation and removal of directing groups， significantly enhancing the atom economy and step economy of the reactions. This review systematically summarizes the progress in transition-metal-catalyzed C―H bond functionalization of amines via transient directing group strategies over the past decade. It focuses on the development and structural characteristics of different types of transient directing groups， and provides a detailed analysis of their applications in arylation， alkynylation， fluorination， oxidation， thiolation， and sulfonylation reactions. Additionally， the review discusses current limitations in the field， including reaction types， cost control， reaction conditions， and stereoselectivity， and prospects future directions such as the design of novel transient directing groups and the construction of new catalytic systems.

Contents

1 Introduction

2 Types and design strategies of transient directing groups

3 TDG-directed C―H functionalization of amines

3.1 Glyoxylic acid-type TDG-directed C―H functionalization of amines

3.2 Salicylaldehyde-type TDG-directed C―H functionalization of amines

3.3 2-Hydroxynicotinaldehyde-directed C―H functionalization of amines

3.4 Aza-aryl aldehyde-type TDG-directed C―H functionalization of amines

3.5 2-Benzoyl-4-chlorotrifluoromethanesulfonanilide directed selective arylation of amines

3.6 Acetal-type TDG-directed C―H functionalization of amines

3.7 Carbon dioxide-directed C―H functionalization of amines

3.8 Pivalaldehyde-directed C―H functionalization of amines

4 Conclusion and outlook

Graphical abstract

Keywords

transient directing group / C―H activation / amine / transition metal / imine / functionalization

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Ying Kang, Zhuoqi Li, Shiming Fan, Shouxin Liu. Transition-Metal-Catalyzed C―H Bond Functionalization of Amines via Transient Directing Group Strategies. Progress in Chemistry, 2026, 38(5): 870-887 DOI:10.7536/PC20250811

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1 Introduction

The synthesis and functionalization of amine molecules represent one of the core research directions in organic chemistry, providing rich molecular structural building blocks and functional diversity for fields such as drug development, materials science, and natural product discovery.[1-4]. As important structural units in pharmaceuticals, amine compounds are widely present in various drugs (Scheme 1). According to statistics, among the top 200 small-molecule prescription drugs by global sales in 2022, 82% contain at least one amino group or nitrogen-containing heterocycle, a figure that fully demonstrates the importance of amine molecules in drug development.[5]In the field of materials, amine compounds are also increasingly widely applied, such as in carbon dioxide capture and resource utilization[6], toxic substance detection and adsorption[7], and optoelectronic material development[2]. Furthermore, amine molecules constitute an extremely important class of natural products in nature[4,8-9]. Therefore, developing new methods for the efficient and highly selective synthesis and modification of amine compounds not only expands the research boundaries of organic synthetic chemistry but also provides an essential molecular toolbox for research in pharmaceuticals, material molecules, natural products, and other fields.
The C―H bond is the most fundamental and widely distributed chemical bond in organic molecules. Direct activation of inert C―H bonds followed by functionalization to construct target molecules can simplify synthetic routes from the source and significantly improve atom economy, making it a core research direction and frontier hotspot in contemporary organic synthesis chemistry. In recent years, this strategy has not only achieved efficient synthesis of various molecules such as sulfides, carboxylic acids, phosphorus compounds, and lactones, but has also been widely applied to the late-stage modification of complex structured molecules and pharmaceuticals, demonstrating huge development potential and broad application prospects.[10-15].
The emergence of transition metal-catalyzed strategies for the functionalization of inert C―H bonds has provided a novel synthetic route for the efficient construction of amine molecules with complex structures and functions[16-20]. Compared with traditional methods for synthesizing amine molecules, such as the reduction of high-valent nitrogen organic compounds, reductive amination of aldehydes and ketones, and nucleophilic substitution of amino groups, transition metal-catalyzed C-H bond functionalization reactions can directly introduce target functional groups onto the inert C―H bonds of simple amine substrates, significantly simplifying synthetic steps and improving reaction efficiency. The core of this strategy lies in how to guide the transition metal to selectively cleave the target C―H bond. In amine compounds, although the nitrogen atoms contained within them can coordinate with transition metals, using the amines themselves directly as directing groups faces the following challenges: (1) Amines have strong coordination abilities and easily form stable bimolecular coordination compounds with transition metals, leading to catalyst deactivation[21]; (2) Metal catalysts may oxidize the C―N single bond in amines to a C$\stackrel{\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }}{̿}$N double bond, triggering side reactions[22-23]; (3) Amino groups possess strong nucleophilicity and are prone to undergoing nucleophilic substitution reactions with electrophilic functionalization reagents (Scheme 2a). Due to these inherent problems, the development of C―H functionalization reactions directly guided by the amines themselves has been slow[20]. To address these issues, chemists have introduced electron-withdrawing directing groups onto the nitrogen atoms of amine substrates to weaken the coordination ability of the nitrogen atoms with transition metals, thereby avoiding catalyst deactivation and achieving activation of the target C―H bonds. The reaction process involves a directing group-guided cyclometalation step that converts the C―H bond into a C―M bond, followed by subsequent functionalization. Based on this strategy, several classic directing groups such as 2-pyridinecarboxamide, sulfonamides, thioamides, pyrazoles, and 2-pyrimidinyl have been successfully developed and applied to C―H bond functionalization reactions of amine compounds[17](Scheme 2b). Although these covalent directing group strategies have achieved significant results, they require additional steps for the pre-installation and removal of the directing groups, which contradicts the fundamental principles of improving atomic and step economy. Furthermore, the connection between the directing group and the substrate amine is generally through an inert amide bond, requiring harsh conditions for removal, which may lead to changes in other sensitive functional groups within the molecule. These factors result in many challenges remaining for their practical application, thus urgently necessitating the development of more efficient and economical catalytic strategies.
In recent years, transition metal-catalyzed C–H functionalization reactions based on the transient directing group (TDG) strategy have achieved significant development. Compared with traditional covalent directing groups, the TDG strategy reversibly binds to substrate molecules via dynamic covalent bonds, guiding the transition metal to precisely locate and selectively cleave the target C–H bond. Upon completion of the reaction, the directing group automatically dissociates in situ to yield the target product. This strategy avoids the pre-installation and subsequent removal of the directing group, significantly improving the atom economy and step economy of the reaction. The TDG strategy has been widely applied in the C–H functionalization reactions of aldehyde compounds.[24-29]. However, applying the TDG strategy to the C–H activation of amine compounds faces more challenges: the presence of a large amount of free amines in the reaction system, whose strong coordination properties easily lead to the formation of stable bimetallic complexes, hindering the catalytic cycle and causing catalyst deactivation; meanwhile, the sensitivity of free amines to oxidants and electrophilic reagents easily triggers side reactions. The existence of these problems has caused the development of TDG strategy-based C–H functionalization of amine compounds to lag behind that of aldehyde and ketone systems. Nevertheless, due to the importance of amine compounds, over the nearly ten years from 2016 to the present, chemists have successfully designed various novel transient directing groups, achieving breakthrough progress in the selective C–H functionalization reactions of amine substrates (Scheme 2c).
Due to the limited number of reports on TDG-directed C―H functionalization reactions of amine compounds in earlier studies, some reviews on C-H activation reactions have only included this topic as a minor section and have not covered all relevant research to date[15,17,20,25-27,30-32]. Recently, due to the advantages and importance of the TDG strategy, related research reports have increased significantly, highlighting huge development potential; therefore, there is an urgent need for a dedicated and comprehensive review to summarize progress and provide forward-looking perspectives. The development of novel transient directing groups is central to this field, as the emergence of a new transient directing group often drives the development of a series of related reactions. From a new perspective on TDG development, this article systematically summarizes the structural characteristics, applicable reaction types, and mechanisms of action of transient directing groups suitable for amine C―H functionalization, deeply analyzes current research limitations, and outlines future trends, providing theoretical references and innovative insights for the subsequent design of novel transient directing groups and research on C―H functionalization of amine compounds.

2 Types and design strategies of transient directing groups

An ideal TDG should possess dual functions: on one hand, it can efficiently and dynamically bind to and dissociate from the substrate amine; on the other hand, it can guide the transition metal to precisely activate the target C―H bond.
Among the TDGs currently developed for C―H functionalization of amine substrates, aldehydes and ketones stand out particularly due to their unique chemical properties: the carbonyl group undergoes reversible nucleophilic addition-elimination with the substrate's amino group, releasing water to form an imine. This process not only constructs the directing group in situ but also spontaneously dissociates after the reaction. Furthermore, aldehydes and ketones offer the following significant advantages: (1) they are widely distributed in nature and exhibit rich structural diversity, providing abundant resources for screening suitable TDGs; (2) their skeletons can be modified by introducing substituents with different electronic and steric properties, allowing fine-tuning of the reactivity of TDGs.
In addition to the ability to reversibly bind with the substrate, the TDG must more importantly guide the transition metal to selectively cleave the target C―H bond. The TDG first forms an imine bond with the amine substrate, using the imine nitrogen atom as a coordination site to chelate with the metal catalyst. To achieve regioselectivity, the TDG molecule usually needs to contain another coordinating group, forming a rigid bidentate chelation mode (five- or six-membered ring structure) with the transition metal. This directs the transition metal to the vicinity of a specific C―H bond on the amine molecule, thereby achieving efficient activation and functionalization of the inert C―H bond with regioselectivity. In the imine intermediate formed between the TDG and the amine, if both coordination sites are strong ligands, they tend to form bis-complexes with the transition metal, leading to catalyst deactivation.[33]. Therefore, when designing a TDG, in addition to providing one coordination site for the transition metal via the imine bond formed between the TDG carbonyl and the amine, the other coordination site is typically a weakly coordinating group, such as a carboxyl group, phenolic hydroxyl group, sulfonamide, or ether, thereby enabling the reaction to proceed with a TDG that forms an effective coordination mode (Scheme 3).
In 2016, the research groups of Ge Haibo, Yu Jinquan, and Dong Guangbin independently developed glyoxylic acid, 2-hydroxynicotinaldehyde, and quinoline-8-carbaldehyde as TDGs, achieving γ-C(sp3)-H arylation of aliphatic amines, officially ushering in the era of TDG-directed C-H functionalization of amine compounds. To date, TDGs developed for C-H functionalization of amine compounds include: glyoxylic acid-type TDGs, salicylaldehyde-type TDGs, 2-hydroxynicotinaldehyde, azaheteroaryl aldehyde-type TDGs, 2-benzoyl-4-chlorotrifluoromethanesulfonanilide, acetal-type TDGs, carbon dioxide, and pivalaldehyde. Among these, the vast majority of TDGs coordinate with transition metals via bidentate coordination, but a very few utilize tridentate coordination, such as diethoxyethyl proline, or monodentate coordination, such as carbon dioxide and pivalaldehyde (Scheme 4).

3 TDG-directed C―H functionalization of amine compounds

3.1 Glyoxylic Acid-Derived TDG-Directed C―H Functionalization of Amine Compounds

As a compound possessing both carboxyl and carbonyl functional groups, glyoxylic acid can form dynamic imine bonds between its carbonyl group and the amino groups of amine substrates, while its carboxyl group forms weak coordination bonds with metal centers. This facilitates the formation of five-membered chelated metal rings, directing transition metal catalysts to specific C―H bonds on the amine molecules.
In 2016, the Ge Haibo group[34]reported the Pd-catalyzed γ-C(sp3)-H arylation of free aliphatic amines using hydrated glyoxylic acid as a transient directing group (Scheme 5). The reaction proceeds smoothly requiring only a catalytic amount of TDG. High selectivity for γ-methyl C(sp3,5]-bicyclic palladium intermediate is achieved to realize C(sp3)-H bond activation. The reaction system is compatible with aliphatic primary amines of different structures; it works for cyclic γ-methylene C-H bonds but not for acyclic ones, and it tolerates aryl iodides containing various electron-withdrawing or electron-donating groups. The reaction mechanism indicates: first, the substrate primary amine reacts with the aldehyde group of glyoxylic acid (TDG) under acid catalysis to generate an imine intermediateI, whose α-imino carboxylic acid coordinates with palladium via bidentate coordination to form intermediateII, which then undergoes concerted metalation-deprotonation (CMD) mechanism to cleave the γ-C(sp3)-H bond, generating a [5,5]-palladacycle intermediateIII. IntermediateIIIundergoes oxidative addition with aryl iodide to generate intermediateIV, followed by reductive elimination to yield the arylated product. Finally, glyoxylic acid dissociates in situ to release the free amine, while glyoxylic acid and the regenerated palladium catalyst enter the next catalytic cycle (Scheme 6).
In the aforementioned study, the Ge Haibo group utilized glyoxylic acid as a TDG to achieve γ-methyl-C(sp3)–H arylation of free aliphatic amines, but did not investigate more remote δ-C(sp3)–H arylation. Given the importance of δ-arylamines in pharmaceutical molecules, in 2018, the Yu Jinquan group[35]developed a palladium-catalyzed δ-methyl-C(sp3)–H arylation reaction of free aliphatic amines using 2-methoxybenzoylformic acid as the TDG (Scheme 7). When aliphatic amines contain both γ-C–H and δ-C–H bonds, the authors propose that there is a specific matching relationship between the size of the chelate ring formed by palladium coordination with different structural TDGs and the size of the cyclopalladated intermediate generated after C(sp3)–H bond activation: when using a TDG that chelates with palladium to form a six-membered ring, the reaction tends to generate a kinetically favorable [6,5]-bicyclic palladium intermediate, thereby activating the γ-C(sp3)–H bond; conversely, if the transition metal forms a five-membered ring with the TDG, the reaction tends to cleave the δ-C(sp5,6]-bicyclic palladium intermediate to break the δ-C(sp3)–H bond. The authors realized that since glyoxylic acid can combine with amines to coordinate with palladium and form a five-membered ring, it is possible to utilize this type of TDG to achieve δ-C(sp5,6]-bicyclic palladium intermediate-mediated activation of the δ-C(sp3)–H bond. After screening different glyoxylic acid derivatives, 2-methoxybenzoylformic acid was identified as the optimal TDG, and by adding a 2-nitropyridone ligand to promote the reaction, the δ-C(sp3)–H arylated product was obtained in 60% yield. The reaction exhibits good compatibility, accommodating both aryl iodides and heteroaryl iodides; when aliphatic amines containing linear or cyclic alkanes are used as substrates, they must possess 1–2 alkyl groups at the γ-position. Notably, even when highly reactive γ-benzylic C–H bonds are present in the amine substrate, this catalytic system can still highly selectively activate the remote δ-C(sp3)–H bond.

3.2 Salicylaldehyde-type TDG-directed C―H functionalization of amine compounds

Salicylaldehyde and its derivatives offer advantages of good commercial availability, simple synthesis, and easy derivatization. Structurally, salicylaldehyde contains adjacent aldehyde and weakly acidic hydroxyl groups on the benzene ring. The salicylaldimine formed by the condensation of its aldehyde group with a primary amine chelates with metals via bidentate coordination between the imino nitrogen and phenolic oxygen to form a six-membered chelate. Due to the presence of the benzene ring, the rigid skeleton of the bidentate ligand in this chelate can precisely position the metal at a specific C―H bond of the amine substrate, activating it to achieve highly regioselective functionalization reactions.[36-38]. Based on these characteristics, using salicylaldehyde compounds as TDGs has successfully achieved C―H arylation and oxidation of aliphatic amines, as well as alkynylation of aromatic amines.
In 2017, the Murakami group[38]reported the use of 3,5-di-tert-butylsalicylaldehyde as a transient directing group to achieve palladium-catalyzed γ-methyl-C(sp3)-H arylation of free primary amines (Scheme 8). In this system, the tert-butyl group at the 3-position of 3,5-di-tert-butylsalicylaldehyde is key to the successful reaction. In the formed chelated complexI, the tert-butyl group exerts a "buttressing effect," restricting the spatial freedom of rotation of the amine molecule's sec-butyl chain and positioning it in a conformation suitable for metalation via a concerted metalation-deprotonation (CMD) mechanism. Furthermore, the presence of the 3-position tert-butyl group effectively suppresses the formation of the inactive bis-imine palladium complex IV, preventing catalyst deactivation and thereby maintaining the catalytic cycle. Substrate scope studies revealed that for amine substrates, an alkyl group must be present at the α-position for the reaction to proceed; this is likely because the steric effect of the α-substituent promotes the formation of a five-membered palladacycle, facilitating the reaction.
The authors proposed the mechanism of this reaction (Scheme 9): The primary amine undergoes dehydration condensation with salicylaldehyde to form an imine intermediate, which coordinates to the palladium center via bidentate chelation through the phenolic hydroxyl group and the imine nitrogen, forming a six-membered chelate complexI. Guided by the steric hindrance of the tert-butyl group at the 3-position, the palladium center activates the γ-C(sp3)―H bond via a CMD mechanism, generating a cyclopalladated intermediateII. Subsequently, oxidative addition of the aryl iodide forms intermediateIII, which finally undergoes reductive elimination to construct the C―C bond and release the γ-arylated product, while regenerating the palladium catalyst for the next catalytic cycle.
In 2018, the Yu Jinquan group[35]developed a synergistic system of 6-chlorosalicylaldehyde TDG and pyridone ligands, achieving palladium-catalyzed heteroarylation of γ-methylene C(sp3)―H bonds in aliphatic primary amines (Scheme 10). The pyridone ligand plays multiple key roles in this system: first, it effectively stabilizes the palladium catalyst through moderate coordination, preventing its deactivation by potential catalyst-poisoning functional groups in the substrate, such as aromatic heterocycles; second, it works synergistically with the TDG to regulate reaction selectivity, guiding the palladium center to precisely identify the target C―H bond; third, it acts as an internal base to lower the activation barrier for C―H bond cleavage, promoting C―H bond breaking. With the assistance of the pyridone ligand, this system is compatible with various heteroaryl iodides, including pyridine, thiophene, pyrimidine, quinoline, benzopyrazine, benzothiazole, and benzopyrimidine. For amine substrates, it efficiently achieves γ-methylene arylation of cyclic amines; even when the substrate simultaneously contains δ-C(sp3)―H bonds, it maintains high functionalization selectivity for the γ-methylene C(sp3)―H bonds.
In 2020, the Hartwig group[39]used salicylaldehyde as a transient directing group to achieve palladium-catalyzed β-C(sp3)―H acetoxylation of free amines (Scheme 11). This reaction proceeds via the formation of a rare four-membered palladacycle intermediate to realize β-C(sp3)―H bond activation. In C―H bond activation steps, stable five- or six-membered metallacycle intermediates are typically formed, thereby enabling functionalization of amine γ- or δ-position C―H bonds. However, due to ring strain, four-membered ring intermediates are kinetically and thermodynamically disfavored, making β-C―H bond functionalization of alkylamine derivatives extremely difficult. To investigate the reason for four-membered ring formation, the authors performed DFT calculations indicating that an intramolecular hydrogen bond between the hydroxyl oxygen of salicylaldehyde and the hydroxyl group of the coordinated acetate is the key factor stabilizing the four-membered palladacycle intermediate. The reaction exhibits good compatibility; tertiary carbon amino compounds containing various substituents such as alkyl ethers, silyl ethers, and ester groups all afford β-acetoxylation products in moderate yields. The regioselectivity and yield of the reaction are closely related to the alkyl structure: when the substrate contains both γ-methyl and β-methyl C―H bonds, acetoxylation preferentially occurs at the γ-methyl site via a five-membered palladacycle intermediate; whereas when a γ-position methylene and a β-position methyl group are present, the reaction site depends on the electronic nature of the substituent on the γ-methylene, with electron-withdrawing groups tending to direct the reaction to the more acidic γ-methylene site.
Most amine C―H bond functionalization reactions based on transient directing groups rely on 4d/5d precious metal catalysts such as palladium and iridium, with palladium catalysis dominating. Although their catalytic performance is excellent, high costs and scarcity limit practical applications. Nickel, as a 3d transition metal, demonstrates significant potential in the field of C―H bond activation due to advantages such as low cost, low toxicity, and abundant reserves, making it an ideal choice to replace precious metal catalytic systems. In 2025, the research groups of Fan Shiming and Liu Shouxin[40]using salicylaldehyde as a transient directing group, achieved nickel-catalyzed γ-C(sp2)―H alkynylation of free benzylamines (Scheme 12). During condition optimization, it was found that salicylaldehyde served as the most effective transient directing group, and the addition of the ligand 2,4,6-trimethylpyridine significantly improved the reaction yield. The reaction exhibits good compatibility; when the benzene ring of benzylamine contains substituents with different electronic properties such as halogens, alkyl groups, or phenyl groups, the reaction proceeds smoothly. Substrates containing heterocycles (such as pyridine, furan, thiophene, and benzo-1,4-dioxane) are also compatible. Substrates with different substituents at the α-position of the amino group can be successfully converted. Finally, studies on alkynylating reagents revealed that the reaction remains compatible when the alkyne bears different silyl protecting groups, phenyl groups, or tert-butyl groups.
Radical trapping experiments indicate that the reaction does not involve a radical pathway; it likely proceeds via a Ni(II)/Ni(IV) catalytic cycle (Scheme 13): TDG first forms an imine intermediate with the amineI, which undergoes Ni(II) coordination and deprotonation to generate intermediateII, followed by γ-C(sp2)―H activation to form a nickellacycle intermediateIII; oxidative addition of the TIPS-protected alkynyl bromide generates the Ni(IV) intermediateIV, and final reductive elimination yields the target product while regenerating the Ni(II) catalyst.
Isoindole compounds have important applications in medicinal chemistry, natural products, and materials science[41-43]. Based on the successful nickel-catalyzed γ-C(sp2)-H alkynylation of free benzylamines[40], the research groups of Fan Shiming and Liu Shouxin[44]further developed a nickel-catalyzed γ-C(sp2)-H alkynylation/hydroamination tandem reaction using salicylaldehyde as a transient directing group, successfully achieving the construction of substituted 1H-isoindoles (Scheme 14). The study found that the trifluoromethylbenzoic acid ligand is a key factor for the smooth occurrence of the tandem reaction: the trifluoromethylbenzoic acid ligand not only efficiently promotes the formation of γ-C(sp2)-H alkynylation but is also crucial for promoting the subsequent hydroamination reaction. Furthermore, the use of the TDG strategy enables the reaction to produce alkynylated free amine intermediates, providing the material basis for the smooth occurrence of the subsequent hydroamination reaction, which is an advantage not possessed by covalent directing groups. When the benzylamine substrate has no substituent at the ortho position, the reaction can undergo ortho-C(sp2)-H dialkynylation of the benzylamine, thereby yielding alkynyl-substituted 1H-isoindole derivatives. The alkynyl group on the 1H-isoindole can serve as an anchoring point to introduce other groups via copper-catalyzed azide-alkyne cycloaddition (CuAAC reaction), thereby preparing relevant functional molecules containing isoindoles.
The authors proposed a possible mechanism for this tandem reaction (Scheme 15): TDG first condenses with the substrate amine1to form the imine intermediateI. Subsequently, amineIundergoes nickel coordination and deprotonation to yield intermediateII, which undergoes C(sp2)―H activation to form the nickellacycle intermediateIII,IIIundergoes oxidative addition with the TIPS-protected bromoalkyne to afford intermediateIV, followed by reductive elimination to generate intermediateV,Vupon protonation yields the alkynylated imineVIand regenerates the nickel catalyst. Subsequently, a second alkynylation occurs to generate the dialkynylated imine intermediateVII,VIIupon hydrolysis releases the free amineVIII.VIIIenters the second catalytic cycle, undergoing intramolecular hydroamination mediated by the nickel catalyst. This step proceeds via two possible mechanistic pathways: one involves alkyne insertion into the metal-amine coordination bond (inner-sphere pathway:IX-X), while the other involves nucleophilic addition of the amine to the coordinated alkyne (outer-sphere pathway:IX'-X'). Subsequent proton transfer releases the enamineXIand regenerates the nickel catalyst. The enamineXIisomerizes to the cyclic imineXII. Finally, intermediateXIIundergoes hydrolysis under acidic conditions to afford the desired product.

3.3 2-Hydroxynicotinaldehyde as a TDG-directed C―H functionalization reaction of amine compounds

2-Hydroxynicotinaldehyde is currently the most widely used transient directing group. Its design inspiration stems from the 2-hydroxypyridine (2-pyridone) ligand, which exhibits similarity to carboxyl groups in their coordination modes with transition metals. Therefore, it can serve as a substitute for carboxyl groups, mimicking the weak coordination of carboxyl groups in TDGs to effectively prevent deactivation of transition metal catalysts.[33,45]. Meanwhile, 2-hydroxynicotinaldehyde possesses a rigid skeleton similar to salicylaldehyde, enabling the precise positioning of the transition metal to the target C―H bond via a six-membered rigid structure to achieve activation. Currently, TDGs based on 2-hydroxynicotinaldehyde have been successfully applied to various types of reactions, including C―H arylation, fluorination, oxidation, and copper-catalyzed sulfonylation of amine compounds (Scheme 16).
In 2016, the Yu Jinquan group[33]used 2-hydroxynicotinaldehyde as a transient directing group to achieve palladium-catalyzed γ-C(sp3)-H arylation of free primary amines (Scheme 17). The reaction exhibited excellent compatibility with various aryl iodides and heteroaryl iodides containing electron-withdrawing and electron-donating substituents. Moreover, it was compatible with the γ-C(sp3)-H arylation of primary amines without α-substituents, cyclic methylene amines, and acyclic methylene amines, with yields reaching up to 91%. Notably, the loadings of the catalyst and the transient directing group could be reduced to 2% and 4%, respectively, fully demonstrating the high efficiency of this newly designed transient directing group.
In 2018, the Kamenecka group[46]used 2-hydroxynicotinaldehyde as a transient directing group to achieve palladium-catalyzed γ-C(sp3)―H and γ-C(sp2)―H site-selective arylation of free amino esters (Scheme 18). The study found that while reactions using glyoxylic acid and salicylaldehyde-type TDGs performed very poorly, 2-hydroxynicotinaldehyde exhibited high reaction efficiency. This reaction demonstrates broad substrate scope, enabling various free amino esters, including α- and β-amino esters, amino monoesters, and amino diesters, to react with diverse aryl and heteroaryl iodide reagents, thereby allowing the rapid synthesis of high-value non-natural amino acids from readily available starting materials.
Fluorine-containing drugs account for a significant proportion of modern pharmaceuticals. Introducing fluorine into drug molecules can modulate molecular conformation, lipophilicity, and metabolic stability, representing an important approach for drug structure modification.[47-48]. As amines are important structural units in drugs, research on the C―H fluorination of amines is of great significance. In 2020, the Yu Jinquan group[49]reported the γ-C(sp3)―H fluorination of free amines via palladium catalysis using 2-hydroxynicotinaldehyde as a transient directing group (Scheme 19). During condition optimization, when salicylaldehyde, which differs from 2-hydroxynicotinaldehyde by only one nitrogen atom structurally, was used as the TDG, the reaction hardly proceeded, indicating a significant difference in their influence on the reaction. The study found that using 5-chloro-3-nitropyridone as the ligand,N-fluorobenzenesulfonimide (NFSI) as the fluorinating reagent, and adding silver trifluoroacetate as an additive, the fluorination reaction could efficiently occur at the γ-methylene-C(sp3)―H bond of the amine; whereas when using 3-bromo-5-(trifluoromethyl)-2-pyridone as the ligand,N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the fluorinating reagent, and without silver salt additives, the fluorination reaction could specifically act on the γ-methyl-C(sp3)―H bond. DFT computational studies indicated that the rate-determining step for methylene fluorination is oxidative addition, while that for methyl fluorination is C―H activation; the silver salt is a key factor regulating the site selectivity of the reaction. The involvement of silver can lower the energy barrier span for methylene fluorination, whereas it leads to an increase in the energy barrier span for methyl fluorination, thereby achieving differentiated activation of the two types of γ-C(sp3)―H bonds.
The authors propose a possible mechanism for the γ-methylene-C(sp3)-H fluorination reaction (Scheme 20): The imine formed between the amine substrate and TDGIcoordinates with Pd to generate the chelateIIand promotes γ-C(sp3)-H activation. DFT calculation results indicate that the C-H cleavage barrier is lowest when TDG acts as a ligand. The formed palladacycle intermediateIIIundergoes ligand exchange and coordinates with Ag+and NFSI to generate the low-energy intermediateIV. Subsequently, Pd(II) undergoes oxidative addition to the N-F bond via a pyridonate ligand-assisted bimetallic transition state, generating the Pd(IV) intermediate V. Ligand axial-equatorial interchange converts intermediateVintoVI, which finally undergoes reductive elimination to yield the fluorinated productVII. In this process, the pyridonate ligand exhibits a dual role: it acts as an acetate substitute to promote C-H cleavage and also plays a bimetallic synergistic role in oxidative addition.
In 2020, the Yu Jinquan group[50]also used 2-hydroxynicotinaldehyde as a transient directing group to achieve palladium-catalyzed γ-C(sp3)-H acyloxylation and alkoxylation of free amines (Scheme 21). In this reaction, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate was used as the oxidant, with organic acids or alcohols serving as nucleophiles, enabling the introduction of acyloxy and alkoxy groups at the γ-position of aliphatic amines. Studies have shown that amines containing α-alkyl groups and unsubstituted aliphatic amines are both applicable to this reaction, which is compatible with various aryl, heteroaryl, and fatty acid reagents, as well as primary, secondary, and tertiary alcohol reagents; however, heteroaryl acids require higher TDG loading to prevent catalyst poisoning. Notably, several important natural products and drugs, such as Ibuprofen, Isozepac, Fenbufen, and Lithocholic Acid, can serve as coupling reagents in this reaction, providing a new avenue for late-stage functionalization (LSF) modification of pharmaceuticals.
As important functional components of various peptides, peptidomimetics, proteins, antibiotics, and other bioactive compounds, β-amino acids are increasingly widely used in the pharmaceutical, agrochemical, and healthcare industries[51-53]. In 2020, the Wang Jiang research group[54]reported the use of 2-hydroxynicotinaldehyde as a transient directing group to achieve palladium-catalyzedβ2-amino esters and β3-amino ester γ-C(sp3)―H arylation reactions (Scheme 22). During condition optimization, it was found that a dual-palladium synergistic catalyst (Pd(OAc)2/Pd(PhCN)2Cl2) could effectively improve the reaction yield. β2-amino esters and β3-amino ester substrates can react with various aryl iodides and heteroaryl iodides, but ortho-methyl substituted aryl iodides are difficult to accommodate due to steric hindrance.
As important scaffolds for natural products and drug molecules, aryl C-glycosides have attracted significant attention in drug development due to their resistance to enzymatic and hydrolytic degradation.[55-56]. In 2023, the Messaoudi group[57]reported the palladium-catalyzed γ-C(sp3)–H arylation of 3-amino sugars using 2-hydroxynicotinaldehyde as a transient directing group (Scheme 23). The key to this reaction lies in the synergistic effect of the pyridone ligand; the 5-bromo-3-nitropyridone ligand containing strong electron-withdrawing substituents significantly enhanced reaction efficiency. This is consistent with the theory proposed by the Yu group that the combination of 2-hydroxynicotinaldehyde and a pyridone ligand can further improve reaction efficiency.[35], especially for substrates containing heteroatoms, where the ligand stabilizes the metal catalyst and prevents its poisoning. Notably, the reaction employs a one-pot "arylation-azidation" strategy, converting the in situ generated amino glycoside intermediate into an azide, which is then efficiently transformed into a C3-triazolo-C-glycoside via CuAAC reaction. This significantly enhances molecular complexity and provides a practical tool for the diverse modification of drug molecule scaffolds.
In 2023, the Bull group[58]utilized 2-hydroxynicotinaldehyde as a transient directing group to achieve copper-catalyzed benzylic amine γ-C(sp2)―H sulfonylation (Scheme 24). This method employs a synergistic catalytic system of inexpensive copper acetate and manganese dioxide to construct C―S bonds, wherein manganese dioxide serves a dual role as both oxidant and base. The method is compatible with various aryl and alkyl sulfonates as well as polysubstituted benzylamines. DFT calculations indicate that the transient directing group facilitates the formation of copper-cycle intermediates by lowering the energy barrier for the CMD-based C―H activation step, followed by conversion via a sulfonyl radical pathway. This strategy provides an atom-economical route for the synthesis of sulfur-containing amine compounds and promotes the sustainable application of 3d metals in transient directing strategies.

3.4 TDG-Directed C―H Functionalization of Amines with Azaaryl Aldehydes

Azaaryl aldehyde-based TDGs include quinoline-8-carbaldehyde and pyridine carbaldehydes. These TDGs form reversible imine bonds between the aldehyde group and the substrate's amino group; the imine nitrogen and the sp2-hybridized nitrogen atom on the pyridine ring form bidentate coordination with the transition metal, inducing the transition metal to approach and activate the target C―H bond, thereby completing the functionalization reaction.
Quinoline derivatives, due to their unique rigid structure and coordination ability, have been widely used as classic covalent directing groups in C―H activation reactions. For instance, 8-aminoquinoline (AQ) connects with carboxylic acid compounds via an amide bond, directing transition metals to selectively cleave the β-C―H bond of the carboxylic acid compounds[59]. In 2016, the research group of Guangbin Dong[60]developed the use of quinoline-8-carbaldehyde (ArQCHO) as a transient directing group to achieve palladium-catalyzed γ-C(sp3)―H arylation of free aliphatic amines (Scheme 25). This strategy involves the in situ generation of an imine intermediate from the carbonyl group in quinoline-8-carbaldehyde and the amino group in the substrate amine; the imine N and quinoline N coordinate with palladium to form a six-membered ring, followed by the formation of a [6,5]-bicyclic palladium intermediate to selectively cleave the aliphatic amine γ-C(sp3)―H and perform subsequent arylation. After the reaction, quinoline-8-carbaldehyde dissociates in situ to yield the target product. The reaction is compatible with various structures of primary, secondary, and tertiary alkyl amines, and can also arylate C―H bonds of cyclic and acyclic methylene groups with different structures in high yields; however, this reaction requires the use of highly reactive diaryliodonium salts as arylation reagents. This system has also been successfully applied to the δ-position C(sp3)―H bond arylation of aniline derivatives, through the formation of a [6,6]-bicyclic palladium intermediate to selectively cleave the aniline derivative δ-C(sp3)―H, completing the δ-position arylation reaction.
In 2025, the research group of Zhang Yanghui[61]reported a copper-mediated ortho-C(sp2)-H thiolation of benzylamines (Scheme 26). This method employs pyridine carboxaldehyde as a transient directing group to achieve efficient C-S bond construction. Condition optimization identified the optimal reaction system as: Cu(OAc)2 (1.5 equiv) as catalyst, pyridine carboxaldehyde (50 mol%) as TDG, pyridine (50 mol%) as additive, reacting in DMSO at 130 °C. The method exhibits good compatibility with aromatic disulfides bearing substituents such as methyl, methoxy, trifluoromethyl, and halogens, as well as various benzylamine substrates, achieving yields up to 84%. Furthermore, α-substituted benzylamines achieve mono-thiolation selectivity due to steric hindrance.
Mechanistic studies indicate (Scheme 27), pyridinecarbaldehyde (TDG) condenses in situ with benzylamine to generate imine intermediateI; Cu(II) coordinates with intermediate I to form chelateII, which subsequently activates the ortho C(sp2)―H bond via a CMD process, generating cyclometalated intermediateIII. The disulfide undergoes single-electron oxidation to generate a phenylthiyl radical, oxidizing Cu(II) in intermediateIIIto Cu(III), forming intermediateIV. IntermediateIVundergoes reductive elimination to generate thiolated intermediateV, releasing Cu(I). Cu(I) is oxidized by the disulfide to regenerate Cu(II), completing the catalytic cycle.

3.5 2-Benzoyl-4-chloro-N-triflylaniline-directed selective arylation of amine compounds

In nature, a large number of amine compounds contain multiple chemically equivalent reactive γ-C―H bonds; for example, when the benzene ring of benzylamine is unsubstituted or only para-substituted, the two γ-C (sp2) ―H bonds have identical chemical environments; in aliphatic amines containing two or three γ-methyl groups, the reactivity of their γ-C (sp3) ―H bonds is also consistent. When these amines undergo γ-C―H bond functionalization, they often generate mixtures of mono-, di-, and poly-functionalized products, significantly reducing selectivity and efficiency. This issue has long constrained the high efficiency and specificity of C―H monofunctionalization reactions of amine compounds. In 2024, the research groups of Fan Shiming and Liu Shouxin[62]developed a transient directing group (TDG), 2-benzoyl-4-chlorotrifluoromethanesulfonanilide, with effective steric hindrance, capable of achieving palladium-catalyzed mono-arylation of free amines at γ-C (sp3) ―H and γ-C (sp2) ―H bonds (Scheme 28). The authors propose that the effective steric hindrance of the TDG is key to limiting secondary C―H bond arylation. Designed starting from salicylaldehyde, the TDG was created by first converting the hydroxyl group to an amino group and introducing an electron-withdrawing sulfonyl group to generate an acidic N―H bond, mimicking a carboxyl group to form weak coordination while simultaneously creating steric hindrance. Subsequently, a phenyl ring was introduced onto the carbonyl group to further enhance the steric effect. Reactions directed by this TDG exhibit excellent mono-arylation selectivity and good substrate compatibility. For a wide range of free amines containing symmetric γ-C (sp3) —H and γ-C (sp2) ―H bonds, mono-arylated products are generated specifically, and the reaction is compatible with various aryl and heteroaryl iodides.
The authors proposed a possible catalytic cycle mechanism for this reaction (Scheme 29a): the substrate first forms an imine with TDG, which activates the γ-C―H bond upon coordination with palladium, followed by oxidative addition and reductive elimination pathways to yield the arylation product. The steric control of TDG over mono-arylation was elucidated using Newman projections; the two bulky substituents in TDG restrict the free rotation of the mono-arylated product, hindering further γ-C―H arylation (Scheme 29b).

3.6 Acetal-type TDG-directed functionalization reactions of amine compounds

Alkyl aldehydes are a widely existing class of aldehyde compounds. In 2018, the Bull group[63]proposed replacing the α-position of an alkyl aldehyde with a heteroatom to enable weak coordination with a transition metal. This forms a five-membered chelate ring that directs the metal close to the target C―H bond, thereby achieving regioselective C―H activation of amine substrates. However, such heteroatom-containing aldehydes are typically unstable and have poor storage stability, limiting their practical application. Therefore, the authors stabilized this structure by generating acetals, developing (2,2-dimethoxyethoxy)benzene and 1-(2,2-dimethoxyethoxy)-4-(trifluoromethyl)benzene as TDGs, achieving palladium-catalyzed γ-C(sp3)―H arylation of free amines (Scheme 30). Such TDGs rapidly hydrolyze to aldehydes during the reaction, which then react in situ with primary amines to form imines that act as directing groups. Using a catalytic amount of commercially available phenoxyacetaldehyde dimethyl acetal as the TDG, this system enables γ-C(sp3)―H arylation of primary amines with aryl iodides containing electron-withdrawing groups, electron-donating groups, and ortho-substituents. It is applicable to substrates including those with long alkyl chains, cycloalkyl-substituted amines, and α,β-branched amines, exhibiting good selectivity. The overall yields are moderate, with a maximum yield of 61%. However, this reaction cannot achieve γ-methylene C(sp3)―H arylation.
The authors propose a possible reaction mechanism (Scheme 31): First, the alkyl acetal hydrolyzes to an aldehyde under acidic conditions, which condenses with the free amine to generate an imine intermediateI, followed by coordination of the oxygen atom to palladium, forming a bidentate chelated structureII,promoting cyclopalladation of the γ-C(sp3)―H bond; subsequent oxidative addition and reductive elimination yieldV, which finally undergoes hydrolysis to generate the arylated product. Furthermore, the study reveals that the resulting amine product can undergo cyclopalladation via ε-C(sp2)―H to form a thermodynamically stable seven-membered palladacycle, leading to catalyst deactivation and thus inhibiting the reaction.
In 2023, inspired by the Bull group, the Sharma group[64]designed an L-proline-based transient directing group: diethoxyethyl-L-proline (DEP). Under the guidance of this TDG, palladium-catalyzed ortho-monoarylation of benzylamines, phenethylamines, and α-aryl amino acids was achieved (Scheme 32). In this reaction, DEP is first converted into an aldehyde, which reacts with the substrate to generate an imine intermediate in situ. In this intermediate, the imine nitrogen, proline nitrogen atom, and carboxyl oxygen atom coordinate together with palladium to form a tridentate chelated structure, thereby directing palladium to activate the ortho C(sp2)―H bond. During condition optimization, it was found that the presence of the carboxyl group in DEP results in significant steric hindrance in the chelate formed with palladium, which may be key to suppressing secondary arylation. This method has been successfully applied to the synthesis of non-natural amino acids, such as ortho-arylated phenylglycine esters and phenylalanine esters.

3.7 Carbon Dioxide-Directed C―H Functionalization of Amine Substrates

Aldehyde and ketone TDGs perform excellently in C–H activation of amines, but C–H reactions with secondary amine substrates are very difficult, and some oxidation-sensitive amine substrates are prone to side reactions. To address these two issues, in 2018, the Young group[65]reported a carbon dioxide-directed palladium-catalyzed γ-C(sp3)–H arylation of amines (Scheme 33). Carbon dioxide contains a C$\stackrel{\mathrm{ }\mathrm{ }\mathrm{ }\mathrm{ }}{̿}$O structure, which can reversibly bind with amines to form carbamate intermediates; these intermediates can direct C–H bond cleavage via the formation of a seven-membered palladium chelate. This reaction has two major advantages: first, it effectively suppresses the oxidation of oxidation-sensitive primary and secondary amine substrates, such as benzylamines; second, it successfully achieves γ-C(sp3)–H arylation of secondary amines. The reaction operation is simple, requiring only the addition of 1–2 equivalents of dry ice into a standard reaction vessel and sealing it to generate sufficient pressure to promote C–H activation. CO2, as an inexpensive and renewable "green" directing group, is released as a gas after the reaction, greatly enhancing the atom economy and step economy of the process.
In 2019, the Young group[66]further extended this strategy to the ortho-C(sp2)−H arylation of benzylamines (Scheme 34). Under the synergistic effect of Pd(OAc)2and AgTFA, various aryl iodides containing electron-withdrawing/electron-donating groups and primary/secondary benzylamines exhibited good reactivity. This method provides a green and efficient pathway for the synthesis of ortho-arylbenzylamines. It can be efficiently applied to the synthesis of the drug molecule Anacetrapib.

3.8 Pivalaldehyde-Directed C―H Functionalization of Amine Substrates

In 2023, the research group of Cong Xuefeng and Hao Na[67]reported an iridium-catalyzed ortho-C(sp2)−H alkynylation of benzylamines using pivalaldehyde as a transient directing group (Scheme 35). After pivalaldehyde reacts with the amine to form an imine intermediate, the steric hindrance of the tert-butyl group promotes directed activation of the ortho-C(sp2)−H bond. This reaction is compatible with benzylamines bearing substituents at the ortho, meta, or para positions, α-methyl/ethyl-substituted benzylamines, and naphthylmethylamines. However, for benzylamines without ortho substitution, the reaction yields a mixture of mono- and di-alkynylated products.

4 Conclusion and Outlook

This article systematically reviews the research progress of the transient directing group (TDG) strategy in transition metal-catalyzed C―H bond functionalization of amine compounds. TDGs achieve transient direction by forming reversible imine bonds in situ between carbonyl groups and substrate amino groups, avoiding the introduction and removal steps of traditional covalent directing groups, thereby significantly improving the atom and step economy of the reactions. Currently developed TDGs include glyoxylic acid derivatives, salicylaldehydes, 2-hydroxynicotinaldehyde, azaheteroaryl aldehydes, 2-benzoyl-4-chlorotrifluoromethanesulfonanilide, acetals, carbon dioxide, and pivalaldehyde, with salicylaldehydes and 2-hydroxynicotinaldehyde being the most widely applied. Utilizing the TDG strategy, C―H arylation, alkynylation, fluorination, oxidation, sulfonylation, and thiolation reactions of amines have been achieved, and some of these reactions have been successfully applied to the synthesis and late-stage functionalization modification of drug molecules, demonstrating broad application prospects.
Although the TDG strategy offers significant advantages, compared to aldehyde compounds, TDGs suitable for amine substrates still suffer from a scarcity of types and lagging development. There remain many unbroken research gaps in this field: (1) The types of reactions achieved so far are limited, with two-thirds of reported cases being arylation reactions; other transformations such as alkylation, alkenylation, halogenation (chlorination, bromination), and amination have not yet been reported; (2) Catalysts are mostly precious metals like palladium and iridium, used in relatively large amounts (approximately 10%), resulting in high costs. Currently, there are only two reported cases of nickel catalysis and two of copper catalysis; therefore, developing inexpensive 3d transition metals as catalysts is an important direction for future research; (3) To date, there have been no reports on TDG-directed asymmetric C―H functionalization of amine compounds, yet chiral amine compounds hold an extremely important position in pharmaceuticals[68]; therefore, developing chiral TDGs to achieve stereoselective C―H functionalization of amine compounds is an extremely urgent task; (4) Reaction conditions are relatively harsh, with temperatures generally ranging from 90 to 140 °C, and some reactions even require conditions exceeding the solvent's boiling point; thus, the development of mild catalytic systems (such as photocatalysis and electrocatalysis) urgently needs exploration; (5) Applications in the synthesis of natural products and pharmaceuticals remain relatively scarce.
Developing novel TDG and catalytic systems is key to overcoming the aforementioned bottlenecks, a field brimming with new challenges and opportunities. With a deeper understanding of reaction mechanisms and catalytic models, TDG strategies are poised for vigorous development, holding promise as powerful tools for the precise modification of amine compounds and driving organic synthesis toward greener and more efficient directions.

References

Publishing order | Descend order by publishing year | Descend order by cited within
[1]

Delyanee M, Akbari S, Solouk A. Eur. J. Med. Chem., 2021, 221: 113572.
[2]

Fu C P, Gu Z K, Tang Y, Xiao Q, Zhang S S, Zhang Y Q, Song Y L. Angew. Chem. Int. Ed., 2022, 61(19): e202117067.
[3]

Sharifzadeh Z, Morsali A. Coord. Chem. Rev., 2022, 459: 214445.
[4]

Jeon H, Kim J H, Kim S. Nat. Prod. Rep., 2024, 41(2): 228.
[5]

Chen J H, Tan C, Rodrigalvarez J, Zhang S, Martin R. Angew. Chem. Int. Ed., 2024, 63(33): e202406485.
[6]

Hamdy L B, Goel C, Rudd J A, Barron A R, Andreoli E. Mater. Adv., 2021, 2(18): 5843.
[7]

Wang Q, Zhu S N, Xi C, Zhang F. Front. Chem., 2022, 10: 814643.
[8]

Wójcik W, Łukasiewicz M, Puppel K. J. Sci. Food Agric., 2021, 101(7): 2634.
[9]

Eiden L E, Hernández V S, Jiang S Z, Zhang L M. Cell. Mol. Life Sci., 2022, 79(9): 492.
[10]

Guillemard L, Kaplaneris N, Ackermann L, Johansson M J. Nat. Rev. Chem., 2021, 5(8): 522.
[11]

Tang L, Hu Q Y, Yang K, Elsaid M, Liu C, Ge H B. Green Synth. Catal., 2022, 3(3): 203.
[12]

Docherty J H, Lister T M, McArthur G, Findlay M T, Domingo-Legarda P, Kenyon J, Choudhary S, Larrosa I. Chem. Rev., 2023, 123(12): 7692.
[13]

Zhang J, Yao L Y, Su J Y, Liu Y Z, Wang Q N, Deng W P. Green Synth. Catal., 2023, 4(3): 206.
[14]

Goethe O F, Zhou D, Zhu X Y, Sevelda P, Szyperek A, Tomanik M. ACS Catal., 2025, 15(11): 9013.
[15]

Grover J, Sebastian A T, Maiti S, Bissember A C, Maiti D. Chem. Soc. Rev., 2025, 54(4): 2006.
[16]

Willcox D, Chappell B G N, Hogg K F, Calleja J, Smalley A P, Gaunt M J. Science, 2016, 354(6314): 851.
[17]

He C, Whitehurst W G, Gaunt M J. Chem, 2019, 5(5): 1031.
[18]

Chen Y J, Huang Z B, Dai C Y, Yang S, Shi D Q, Zhao Y S. Org. Lett., 2021, 23(11): 4209.
[19]

Sinha S K, Ghosh P, Jain S, Maiti S, Al-Thabati S A, Ali Alshehri A, Mokhtar M, Maiti D. Chem. Soc. Rev., 2023, 52(21): 7461.
[20]

Tao Y, Guo K G, Chen H, Yan G B, Guo M. Org. Chem. Front., 2024, 11(11): 3270.
[21]

Vicente J, Saura-Llamas I, Palin M G, Jones P G, Ramírez de Arellano M C. Organometallics, 1997, 16(5): 826.
[22]

Largeron M. Eur. J. Org. Chem., 2013, 2013(24): 5225.
[23]

Ryland B L, Stahl S S. Angew. Chem. Int. Ed., 2014, 53(34): 8824.
[24]

St John-Campbell S, Bull J A. Org. Biomol. Chem., 2018, 16(25): 4582.
[25]

Higham J I, Bull J A. Org. Biomol. Chem., 2020, 18(37): 7291.
[26]

Wu Y J, Shi B F. Chin. J. Org. Chem., 2020, 40(11): 3517.
[27]

Goswami N, Bhattacharya T, Maiti D. Nat. Rev. Chem., 2021, 5(9): 646.
[28]

Amistadi-Revol H, Liu S S, Prévost S. Eur. J. Org. Chem., 2023, 26(31): e202300582.
[29]

Dong S F, Li H L, Qin Y, Fan S M, Liu S X. Chin. J. Org. Chem., 2023, 43(7): 2351.
[30]

Bhattacharya T, Pimparkar S, Maiti D. RSC Adv., 2018, 8(35): 19456.
[31]

Kapoor M, Singh A, Sharma K, Hua Hsu M. Adv. Synth. Catal., 2020, 362(21): 4513.
[32]

Jacob C, Maes B U W, Evano G. Chem. Eur. J., 2021, 27(56): 13899.
[33]

Wu Y W, Chen Y Q, Liu T, Eastgate M D, Yu J Q. J. Am. Chem. Soc., 2016, 138(44): 14554.
[34]

Liu Y B, Ge H B. Nat. Chem., 2017, 9(1): 26.
[35]

Chen Y Q, Wang Z, Wu Y W, Wisniewski S R, Qiao J X, Ewing W R, Eastgate M D, Yu J Q. J. Am. Chem. Soc., 2018, 140(51): 17884.
[36]

Hiraki K, Ibaraki S, Onishi M, Ono Y, Kawashima J K, Ando M. J. Organomet. Chem., 1997, 547(2): 199.
[37]

Ren Z, Dong G B. Organometallics, 2016, 35(8): 1057.
[38]

Yada A, Liao W Q, Sato Y, Murakami M. Angew. Chem. Int. Ed., 2017, 56(4): 1073.
[39]

Su B, Bunescu A, Qiu Y H, Zuend S J, Ernst M, Hartwig J F. J. Am. Chem. Soc., 2020, 142(17): 7912.
[40]

Cai X H, Ma C, Kang Y, Ren Y Q, Meng X, Lu W, Fan S M, Liu S X. Chin. Chemical Lett., 2025, 36(10): 110901.
[41]

Fazio E, Jaramillo-García J, de la Torre G, Torres T. Org. Lett., 2014, 16(18): 4706.
[42]

Wang X, Weintraub R A. Synthesis, 2023, 55(4): 519.
[43]

Díaz-Jiménez À, Monreal-Corona R, Solà M, Poater A, Roglans A, Pla-Quintana A. ACS Catal., 2024, 14(10): 7381.
[44]

Cai X H, Lu W, Ma C, Kang Y, Ren Y Q, Meng X, Craik D J, Fan S M, Chan L Y, Liu S X. Chin. J. Chem., 2025, 43(23): 3171.
[45]

Wang P, Farmer M E, Huo X, Jain P, Shen P X, Ishoey M, Bradner J E, Wisniewski S R, Eastgate M D, Yu J Q. J. Am. Chem. Soc., 2016, 138(29): 9269.
[46]

Lin H, Wang C, Bannister T D, Kamenecka T M. Chem. Eur. J., 2018, 24(38): 9535.
[47]

Ali S, Zhou J. Eur. J. Med. Chem., 2023, 256: 115476.
[48]

Du Y L, Bian Y P, Baecker D, Dhawan G, Semghouli A, Kiss L, Zhang W, Sorochinsky A E, Soloshonok V A, Han J L. Chem. Eur. J., 2025, 31(25): e202500662.
[49]

Chen Y Q, Singh S, Wu Y W, Wang Z, Hao W, Verma P, Qiao J X, Sunoj R B, Yu J Q. J. Am. Chem. Soc., 2020, 142(22): 9966.
[50]

Chen Y Q, Wu Y W, Wang Z, Qiao J X, Yu J Q. ACS Catal., 2020, 10(10): 5657.
[51]

Yokoo H, Hirano M, Misawa T, Demizu Y. ChemMedChem, 2021, 16(8): 1226.
[52]

Bąchor U, Mączyński M. Molecules, 2021, 26(2): 438.
[53]

Kudo F. J. Antibiot., 2024, 77(8): 486.
[54]

Wang Z H, Fu Y J, Zhang Q Y, Liu H, Wang J. J. Org. Chem., 2020, 85(12): 7683.
[55]

Kitamura K, Ando Y, Matsumoto T, Suzuki K. Chem. Rev., 2018, 118(4): 1495.
[56]

Liu C F. Molecules, 2022, 27(21): 7439.
[57]

Ghouilem J, Bazzi S, Grimblat N, Retailleau P, Gandon V, Messaoudi S. Chem. Commun., 2023, 59(17): 2497.
[58]

Higham J I, Ma T K, Bull J A. Org. Lett., 2023, 25(28): 5285.
[59]

Corbet M, De Campo F. Angew. Chem. Int. Ed., 2013, 52(38): 9896.
[60]

Xu Y, Young M C, Wang C P, Magness D M, Dong G B. Angew. Chem. Int. Ed., 2016, 55(31): 9084.
[61]

Mei M S, Yi D S, Meng F Y, Tang J H, Zhang Y H. Org. Lett., 2025, 27(24): 6284.
[62]

Dong S F, Cai X H, Ma C, Li H L, Kang Y, Feng J, Fan S M, Liu S X. Org. Lett., 2024, 26(29): 6153.
[63]

St John-Campbell S, Ou A K, Bull J A. Chem. Eur. J., 2018, 24(67): 17838.
[64]

Panda S S, Sharma N K. Org. Biomol. Chem., 2023, 21(7): 1468.
[65]

Kapoor M, Liu D, Young M C. J. Am. Chem. Soc., 2018, 140(22): 6818.
[66]

Kapoor M, Chand-Thakuri P, Young M C. J. Am. Chem. Soc., 2019, 141(19): 7980.
[67]

Zhou J, Jiao T G, Fu Q, Wang J, Lu J, Yang L, Wei J, Wei S P, Cong X F, Hao N. Chem. Commun., 2023, 59(42): 6355.
[68]

McVicker R U, O’Boyle N M. J. Med. Chem., 2024, 67(4): 2305.

Funding

National Natural Science Foundation of China(21978067)

Natural Science Foundation of Hebei Province(H2020208030)

Excellent Going Abroad Expert’s Training Program in Hebei Province(201940)

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