Silver-Catalyzed C(sp³)–H Functionalization

Abstract

Silver catalysis has emerged as a versatile tool for C­(sp³)–H bond functionalization, offering unique opportunities to transform simple hydrocarbons into valuable products. Both activated and unactivated C­(sp³)–H bonds have been investigated in recent years. However, most studies have focused on activated bonds. In these protocols, in situ generation of nitrene intermediates has dominated the field, enabling efficient and selective C­(sp³)–H bond transformations. These reports demonstrate that ligand design, in addition to the nature of the silver catalyst, plays a crucial role in achieving chemo-, site-, and even stereoselectivity. During the past decade, silver-catalyzed functionalization has been used for the conversion of C­(sp³)–H bonds into C–C, C–N, C–O, and C–X (X = halogen) bonds. These protocols have shown that Ag­(I) combined with suitable oxidants can be used as a powerful synthetic tool for the functionalization of specific C­(sp³)–H bonds into desired C–Z bonds. This review highlights the advances and limitations in silver-catalyzed C­(sp³)–H functionalization that have been reported during the past decade.

1. Introduction

Silver, or argentum (Ag), which means “white” or “shining”, belongs to Group 11 of the periodic table, together with Cu, Au, and Rg. It is traditionally referred to as a noble metal because of its low reactivity and resistance to oxidation. In its metallic form, silver is a relatively soft and highly ductile metal that exhibits the highest electrical and thermal conductivity, as well as the greatest reflectivity, of all metals. In terms of ionization energy, silver has the lowest first ionization energy in the group (731 kJmol^–1), while its second ionization energy (2073 kJmol^–1) is the highest relative to the other elements of the group. This property causes silver compounds to be mainly limited to the +1 oxidation state. Indeed, the most common oxidation state of silver is Ag­(I), whereas Ag­(II) and Ag­(III) are strong oxidants and are not very common.

Historically, silver, along with other coinage metals, has been used for coinage and jewelry. However, the use of silver as a catalyst in the early 20th century for the oxidation of ethylene to ethylene oxide paved the way for broader catalytic applications. Since then, the application of silver in different forms, both as homogeneous and heterogeneous catalysts, has steadily increased in organic chemistry. Especially in the past decade, silver complexes have been widely reported as efficient catalysts in a variety of chemical reactions. −

C­(sp³)–H bond functionalization can be considered the most important subfield within the broader area of C–H functionalization. − However, the functionalization of C­(sp³)–H bonds faces two major challenges: (1) their intrinsically low reactivity and (2) achieving selective functionalization. The latter, i.e., fine-tuning reaction conditions by identifying appropriate catalysts, ligands, and additives to selectively cleave and functionalize a specific C­(sp³)–H bond, poses a greater challenge in catalytic and synthetic chemistry. Many C­(sp³)–H bonds exhibit similar reactivities and bond dissociation energies, making it difficult to exclusively target a single bond within a given molecule. To address these challenges, various catalysts, including transition metals, have been explored for the selective transformation of C­(sp³)–H bonds. Among them, silver has been shown to be a particularly effective catalyst.

Literature review indicates that silver has been an effective catalyst for C–H bond functionalization reactions, a class of transformations that has steadily grown in importance since the beginning of the current century. , So far, Ag-catalyzed C­(sp)–H and C­(sp²)–H functionalization reactions have been reviewed. However, an exclusive review on silver-catalyzed C­(sp³)–H functionalization is still missing. This review discusses the progress made in silver-catalyzed C­(sp³)–H bond functionalization over the past decade (2016–2025) (Figure ). ,

1.

(a, b) Scope of reviews on silver-catalyzed C­(sp³)–H functionalization.

2. Silver-Catalyzed C(sp³)–H Functionalization

Over the past decade, silver-catalyzed C­(sp³)–H functionalization methods have undergone remarkable development. Compared to other commonly used transition metals in C­(sp³)–H functionalization reactions, silver can coordinate with a wide range of ligands, leading to the formation of diverse complexes. This tunability can be achieved by varying the ligand, counteranion, solvent, and Ag/ligand ratio. In addition, silver exhibits dynamic behavior in solution, which can be leveraged to fine-tune C­(sp³)–H functionalization reactions. This versatility enables silver to act as a powerful catalyst for the selective activation and functionalization of different types of C­(sp³)–H bonds through catalyst control.

Figure provides an overview of the major milestones achieved in this field over the past decade, as well as a summary of the key proposed intermediates. For the purpose of this review, these advances can be categorized from different perspectives, such as catalysts/ligands, reagents, and substrates. However, for clarity and readability, the following sections are organized according to the types of C­(sp³)–H bonds, which can be broadly divided into two main classes: activated and unactivated C­(sp³)–H bonds.

2.

(a) Milestones of silver-catalyzed C­(sp³)–H functionalization during the past decade and (b) overview of current pathways and key intermediates.

2.1. Activated C­(sp³)–H Bonds

Activated C­(sp³)–H bonds are those with lower bond dissociation energies (BDEs), making them relatively easy to manipulate. In this context, two types of hydrogens can be distinguished: “acidic” and “nonacidic.” Acidic hydrogens can be readily manipulated using appropriate bases. Therefore, they are not covered in this review. − In contrast, “nonacidic” hydrogens require more sophisticated approaches, which fall within the scope of this review (Figure ).

3.

Different types of activated C­(sp³)–H bonds.

2.1.1. C–N Bond Formation

Amination of C­(sp³)–H bonds is a common strategy to transform simple hydrocarbons into valuable amine derivatives. Considering the published work in this field, silver-catalyzed amination of C­(sp³)–H bond procedures mostly have exploited the nitrene transfer strategy. A well-known pathway that has been reported by many other catalysts, including Rh, Ru, Co, Cu, Os, and Fe.

Ag­(I), the most common oxidation state of silver, possesses two key features that enable the development of novel methods for the amination of C­(sp³)–H bonds via nitrene transfer. First, Ag­(I) can adopt a wide range of coordination geometries, from linear to octahedral. This structural versatility provides an opportunity to fine-tune reactivity by varying the number and type of ligand, as well as the solvent environment. Second, Ag­(I) exhibits dynamic behavior, which can act as a double-edged sword, offering both advantages and disadvantages depending on the reaction pathway.

In general, silver-catalyzed nitrene transfer amination of C­(sp³)–H bonds proceeds through the following steps: (1) oxidation of the nitrene precursor by an oxidant such as iodosobenzene (PhIO), (2) reaction of the catalyst with the oxidized nitrene to generate a metal-nitrene reactive intermediate, (3) insertion of the generated nitrene species (singlet or triplet) into the C­(sp³)–H bond, and (4) cleavage of the nitrogen–metal bond yielding the corresponding amine (Figure ).

4.

General mechanism for silver-catalyzed nitrene transfer C­(sp³)–H bond amination.

In 2016, Schomaker’s research group unveiled an approach for the intramolecular amination of benzylic, allylic, and propargylic C­(sp³)–H bonds over 3° aliphatic C­(sp³)–H bonds using [Ag­(Py₅Me₂)­OTf]₂ as a catalyst (Scheme ). They previously had reported similar procedures on silver-catalyzed intramolecular amination of sulfamates and amidates, with limited site selectivity. To overcome this challenge, the authors initially attempted to rigidify the ligand framework in order to minimize its dynamic behavior. Although this method did not produce the desired outcome, it was later shown to be effective in other contexts. As a second strategy, they introduced ligand bridging, which successfully delivered the intended site selectivity because it appears that this technique could discriminate between activated methylene C­(sp³)–H bonds (benzylic, allylic, and propargylic) and sterically hindered and yet electron-rich 3° aliphatic C­(sp³)–H bonds. The authors attributed this elevated site selectivity to the structure of the ligand and dimeric nature of [Ag­(Py₅Me₂)­OTf]₂.

1. Silver-Catalyzed Intramolecular Amination of C­(sp³)–H Bonds.

Although previous protocols enabled the chemo- and regioselective intramolecular amination of the target C­(sp³)–H bonds, poor diastereoselectivity in the products remained a major limitation. Indeed, if the starting materials were not diastereomerically pure, then the products were obtained as mixtures of diastereomers. One year later, the authors addressed this challenge by introducing a modified protocol that oxidized the amine to the corresponding imine, followed by nucleophilic addition to afford tertiary amines with the desired diastereoselectivity.

In 2016, Schomaker et al. developed a protocol for the first example of nondirected intermolecular chemoselective amidation of allylic positions using alkylsulfamates as the nitrene precursor and (tpa)­AgOTf as the catalyst (Scheme ). They observed that by changing the ligand from tris­(2-pyridylmethyl)­amine (tpa) to 4,4′-di-tert-butyl-2,2′-bipyridine (^tBubpy), the chemoselectivity of the reaction could be altered, shifting the outcome from allylic amination to double bond aziridation. However, for highly substituted substrates, aziridation is the predominant reaction, regardless of the ligand employed. In general, this work complements their previous findings, saying amination/aziridation of C­(sp³)–H bonds via nitrene transfer reactions can be tuned through changing the ligand/silver ratio. , Later, it was approved that this preferability can be considered as a result of steric differences at C­(sp³)–H and double bond positions. Although this work paved the way for further advances in the intramolecular amination of C­(sp³)–H bonds via a nitrene transfer pathway, is still required to improve the overall reaction efficiency in this field.

2. Silver-Catalyzed Intermolecular Amination of C­(sp³)–H Bonds.

To gain further insight into the reaction mechanism, the authors performed computational analyses and found that the tunable chemoselectivity observed with the two employed ligands resulted from steric hindrance around the Ag–nitrene intermediate. Two possible pathways exist for the amination of C­(sp³)–H bonds: concerted and stepwise. In the concerted pathway, simultaneous C–N and N–H bond formation and C–H cleavage occur via a triangular intermediate. In contrast, the stepwise pathway proceeds through a hydrogen atom transfer (HAT) and a linear N···H···C structure, leading to a radical intermediate. Silver complexes are electron-rich and therefore well-suited to promote the HAT mechanism over the concerted mechanism in the amination of C–H bonds.

In their previous studies, Schomaker’s group observed that amination was moderately favored at α-conjugated C–H bonds over tertiary alkyl positions. To further investigate other factors affecting the site selectivity of the reaction, they focused on noncovalent interactions (NCIs). Repulsive NCIs between the catalyst and substrates play a key role in the amination of two competing C­(sp³)–H bonds via metal-catalyzed nitrene transfer reactions. However, the key question was whether attractive NCIs could be exploited to alter or even override C­(sp³)–H bond amination selectivity. In 2017, Schomaker et al. published a related study describing the role of attractive NCIs in inverting steric effects. They demonstrated that unsaturated units in substrates and phenyl rings in ligands (π···π interactions), as well as silver interactions with unsaturated units in substrates (Ag···π interactions), lower the energy of the directed transition state and reaction conformers, facilitating C­(sp³)–H bond functionalization at the target position (Figure ).

5.

Silver and ligand interactions.

One of the main goals in silver-catalyzed nitrene transfer is to develop a tunable catalyst capable of controlling the chemo-, site-, and stereoselectivity of the amination reaction. This challenge remains unresolved because many factors influence the reaction outcome. Some of these factors are catalyst-related, such as the metal identity, steric hindrance, the metal-to-ligand ratio, and even the fluxionality of the catalyst structure, while others depend on the substrate, including the steric environment and the type and strength of the C–H bond. The aforementioned studies paved the way for advancing C­(sp³)–H amination via silver-catalyzed nitrene transfer to the next level, enabling chemoselective amination of C­(sp³)–H bonds over double bonds, site-selective amination at less hindered positions, and transformations at C­(sp³)–H sites with different bond strengths. Nevertheless, achieving fully controllable C­(sp³)–H amination via nitrene transfer remains a significant challenge. To address some of these issues, in 2019, Schomaker and co-workers reported a study describing the synthesis of β- and γ-amino alcohols through tunable and selective amination of C­(sp³)–H substrates (Scheme ). Using AgClO₄ as the catalyst and dmbox and Py₅Me₂ as ligands, the authors successfully demonstrated that it is possible to selectively target either β- or γ-C–H bonds, leading to different amidates, namely, six-membered and five-membered oxazinanones. These cyclic amidates can then be readily converted into the corresponding 1,2- and 1,3-amino alcohols, which have many applications ranging from pharmaceuticals and agrochemicals to the synthesis of chiral ligands for use in selective catalysis. ,

3. β- and γ-Amination of C­(sp³)–H Bonds Using AgClO₄ as a Catalyst.

This protocol provided an opportunity to control the location of C­(sp³)–H bond amination, either at the weaker benzylic/allylic C­(sp³)–H bonds or at the stronger aliphatic C­(sp³)–H bonds. In other words, by tuning the reaction conditions through ligand modification, it became possible to favor the amination of aliphatic C­(sp³)–H bonds (BDE > 90 kcal/mol) over the typically more reactive benzylic/allylic C­(sp³)–H bonds (BDE ∼ 80–85 kcal/mol). Thus, this protocol can override the inherent reactivity of C­(sp³)–H bonds and enable the selective installation of an amino group at the desired position. According to the authors’ suggestion, this reactivity can be rationalized by considering the steric hindrance of the employed ligand. A less bulky ligand such as dmbox favors the formation of an expanded seven-membered transition state, whereas the more sterically demanding ligand (py₅Me₂) favors a more compact six-membered transition state, leading to six- and five-membered cyclic products, respectively (Figure ). Also, this protocol provides the opportunity to select and functionalize one desired C­(sp³)–H bond between two C­(sp³)–H bonds with similar strength. The authors also extended their findings to the sulfamidation of benzylic and homobenzylic C­(sp³)–H bonds, affording five- and six-membered benzosultam rings.

6.

Silver and ligand interactions.

As the next milestone in silver-catalyzed nitrene transfer amination of C­(sp³)–H bonds, , Schomaker’s group aimed to establish a practical protocol for the enantioselective amination of these bonds. In 2020, they reported a protocol for the enantioselective amination of propargylic C­(sp³)–H bonds using AgClO₄ and bis­(oxazoline) ((S,S)-Min-BOX) as the catalyst and ligand, respectively. However, this method failed to be extended to asymmetric amidations of benzylic, allylic, and unactivated methylene C–H bonds. The authors attributed this limitation to the restricted modularity of the Min-BOX ligand synthesis. To overcome this challenge, they recently reported a new protocol for Ag-catalyzed enantioselective amidation of benzylic, allylic, and unactivated C–H bonds, achieving high yields and enantiomeric excesses (ee) up to 98% (Scheme ). In this study, they designed a series of (S,S)-Min-BOX ligands with two key features to facilitate enantioselective transformation: (1) fully substituted stereocenters within the oxazoline rings and (2) substantial steric bulk imparted by large substituents. Although this approach promotes chemo-, site-, and enantioselective amination at specific positions, it remains unclear whether it can override the intrinsic reactivity of C–H bonds, particularly in challenging cases involving C–H bonds with different reactivities, such as two competitive γ-C–H bonds. Computational studies suggested that the observed selectivity with (S,S)-Min-BOX arises from stabilizing C–H/π interactions as well as distortion interactions between the ligand and the substrates. A decrease in these interactions was correlated with reduced enantiomeric excess (ee), further supporting the critical role of ligand–substrate interactions in dictating selectivity.

4. Enantioselective Amination of C­(sp³)–H Bonds Using AgClO₄ as a Catalyst.

Building on their achievement in silver-catalyzed C­(sp³)–H amination, Schomaker’s group pursued additional studies. These efforts encompassed the identification of alternatives to common chlorinated solvents, the amination of electron-deficient heterobenzylic C–H bonds, and the utilization of carbamates as functionalization agents.

Literature reports show that in addition to the significant contribution of Schomaker’s group on silver-catalyzed C­(sp³)–H bond amination, other groups have also participated in this field. For example, in 2020, Nemoto et al. reported a silver-catalyzed site- and chemoselective functionalization of C­(sp³)–H bonds for the synthesis of spiroaminals, which are important motifs in natural product synthesis (Scheme ). Previous studies with rhodium catalysts had shown a preference for nitrene insertion into the amide C–N bond rather than C­(sp³)–H bonds, leading to diazacyclic units. , However, Nemoto and co-workers demonstrated that silver catalysts could invert this selectivity in favor of C­(sp³)–H amination.

5. Synthesis of Spiroaminals through Amination of C­(sp³)–H Bonds.

Nitrene transfer has been the primary strategy for silver-catalyzed amination of C­(sp³)–H bonds during the past decade, but it is not the only available solution. In 2019, Ge and co-workers reported a synthetic method for the intramolecular cyclization of 2-methylthiobenzamide using silver oxide as the catalyst and Selectfluor as the oxidant reagent (Scheme ). In this reaction, the amide group can replace the benzylic hydrogen through either its oxygen or nitrogen atom, leading to the formation of benzooxathiin-4-imine and benzothiazin-4-one, respectively. Interestingly, while silver oxide and Selectfluor alone favored benzylic C­(sp³)–H amination, the addition of sodium acetate as a base promoted benzylic oxygenation. This can be rationalized by the increased resonance contribution of the amide nitrogen with the carbonyl upon protonation, which enhances the likelihood of oxygen attack at the benzylic position. Furthermore, the authors demonstrated that the initially formed benzooxathiin-4-imine could be readily converted into the corresponding benzooxathiin-4-one under acidic conditions.

6. Ag-Catalyzed Intramolecular Cyclization of 2-Methylthiobenzamides.

To gain further insight into the reaction mechanism, the authors carried out a series of control experiments. One of these involved the use of (2,2,6,6-tetramethylpiperidin-1-yl)­oxyl (TEMPO) to trap potential radical intermediates. Based on the results, they proposed the following pathway. In the first step, Selectfluor promotes the generation of an F–Ag­(III) species through oxidative insertion. In the next step, F–Ag­(III) oxidizes the substrate (7 - 1) into intermediate A, leading to the formation of F–Ag­(II). Then, A converts to B through losing a proton. A 1,6-hydrogen shift transforms B into the radical species C. Subsequently, Ag­(II)-mediated oxidation of C produces intermediate D, which exists in equilibrium with intermediate E. Cyclization of these intermediates furnishes the benzothiazin-4-one product. In the presence of a base, however, intermediate E can diverge into an alternative pathway to afford the benzooxathiin-4-imine product (6-4), which can subsequently be hydrolyzed to the corresponding benzooxathiin-4-one (6-8).

Taken together, the discussed studies highlight two main pathways for C–H amination using silver catalysts: the nitrene intermediate and the radical mechanisms. Over the past decade, the nitrene pathway has been central to silver-catalyzed C­(sp³)–H amination. Unlike the radical pathway, which mostly relies on the inherent reactivity of C–H bonds, this strategy enables the functionalization of target C–H bonds regardless of their innate reactivity. Within this pathway, various approaches have been developed to achieve chemo-, site-, and enantioselectivity in nitrene transfer functionalization. It has been shown that bulky and rigid ligands can enhance both site- and chemoselectivity by stabilizing silver species and modulating their dynamic behavior, thereby enabling discrimination between different positions and C­(sp³)–H bonds. Ligand design has proven so effective that it can deliver highly stereoselective amination or even reverse the favored amination site toward stronger C–H bonds. In other words, the position of C–H bond functionalization can be fine-tuned by adjusting the catalyst–ligand combination, without relying solely on the intrinsic reactivity of the C–H bonds. However, none of the reported methods provide a comprehensive solution that simultaneously addresses chemo-, site-, and stereoselectivity in a broadly applicable manner while also being capable of overriding the innate reactivity of substrates. Developing such a versatile and general protocol remains an open challenge for future research.

2.1.2. C–C Bond Formation

The carbon–carbon bond can be considered one of the most important pillars of organic chemistry. Various transition metals have been employed for direct conversion of C­(sp³)–H bonds into the corresponding C–C bonds. , Among the reported transition metals, silver-catalyzed conversion of C­(sp³)–H bonds to C–C bonds has been far less explored over the past decade compared to silver-catalyzed C­(sp³)–H amination. Nevertheless, the available studies still provide valuable insights into recent advancements in this field.

As a suitable oxidant for numerous C–H functionalization reactions involving radical intermediates, , Selectfluor can be used in C­(sp³)–H functionalization reactions through C–C bond formation. In 2019, Baxter et al. developed a catalytic approach for radical benzylation of quinone using Selectfluor and Ag­(I) as an oxidant and catalyst, respectively (Scheme ). The authors tested different ligands to find the optimum condition for the reaction, and the best results were achieved for Ag­(4-OMePy)₂NO₃. However, the achieved yields for the products were low to average. In fact, except for the reactions of p-quinone and p-xylene, the yields for other combinations were below 60%. Also, there are many examples of unreacted substrates, reflecting the limited applicability of this protocol to a wide range of substrates.

7. Silver-Catalyzed Benzylation of Quinones.

According to the proposed mechanism, Ag­(I) reduces Selectfluor to generate the corresponding cation radical. This radical then oxidizes the alkylbenzene precursor (7-1) to form the corresponding benzyl radical (A), which can be intercepted by quinone to afford an intermediate (B). Finally, Ag­(II) oxidizes radical intermediate B, delivering the desired product (7-3).

With the growing interest in this field, other researchers have also attempted to employ quinone derivatives as functionalization agents for different types of activated C­(sp³)–H bonds. In 2020, Ilangovan and Pandaram introduced another silver-catalyzed C­(sp³)–H functionalization reaction using quinones as functionalization agents (Scheme ). They had previously reported that a AgNO₃/K₂S₂O₈ system could be applied for the functionalization of C­(sp²)–H bonds in quinone derivatives. In their follow-up study, they employed AgNO₃/tert-butyl hydroperoxide (TBHP) as the catalyst/oxidant pair to promote C­(sp³)–C­(sp²) bond formation between quinone derivatives and N-methyl amides. Although the method extends Baxter’s findings to other types of C­(sp³)–H substrates (i.e., α-C­(sp³)–H bonds to nitrogen), the applicability of the reaction to various precursors is severely restricted. In fact, testing different quinones revealed that any substitution on the quinone scaffold significantly decreases the reaction yield and increases the reaction time. This was also the case when N-ethyl amides were employed as C­(sp³)–H precursors, showing that steric hindrance strongly affects the reaction efficiency.

8. Silver-Catalyzed Benzylation of Quinones.

According to the authors’ mechanistic proposal, a tert-butoxyl radical, generated through silver-assisted thermal homolysis of TBHP, converts the amide precursor into a radical–cation intermediate, which is subsequently trapped by the double bond unit of the quinone. Finally, oxidation of the intermediate C by tert-butoxyl radical furnishes the desired product (8-3).

Quinones are not the only functionalization agent that has been used in silver-catalyzed reactions to replace a hydrogen atom in a C­(sp³)–H bond. Literature review demonstrates that there is a huge potential for other compounds to be used in this role. For example, in 2019, Xu and co-workers disclosed a silver-catalyzed conversion of isocyanates into the corresponding iminonitriles and tetrahydroisoquinolines via C­(sp³)–H functionalization (Scheme ). The protocol employed isocyanates as both the cyanide and imine sources, with AgOTf and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) serving as the catalyst and oxidant, respectively. The results showed that for substrates with a single activated C­(sp³)–H bond, only monoimination occurs, whereas for substrates bearing geminal C­(sp³)–H bonds, double imination or a combination of imination and cyanation are the major products.

9. Synthesis of Iminonitrile-Decorated Phenanthridines and Azapyrenes Using AgOTf-DDQ as a Catalyst-Oxidant.

Although this protocol extends silver-catalyzed C–H functionalization to the use of novel functionalization agents (isocyanates) and oxidants (DDQ), it also has its own limitations. For example, substrates bearing strong electron-withdrawing groups (EWGs) such as CF₃ and CN on the aryl ring are not suitable precursors for this transformation. In addition, substrates with moderately electron-withdrawing substituents, such as halogens, exhibited only low efficiency.

To gain mechanistic insight, the authors employed electrospray ionization mass spectrometry (ESI-MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS), which suggested that a nitrilium/oxonium ion may serve as a key intermediate in the reaction pathway. Notably, the reaction was not inhibited by the addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to the reaction mixture, indicating that a radical pathway is unlikely. Although the exact reaction mechanism has yet to be fully elucidated, the authors proposed a preliminary mechanistic pathway involving DDQ-assisted generation of a benzoxy cation intermediate (A). The subsequent addition of isocyanide to A leads to the formation of the corresponding nitrilium ion (B). Addition of a second isocyanide to intermediate B results in intermediate C, which can afford D via loss of a tert-butyl cation. DDQ then rapidly converts D to the corresponding benzylic cation E, which can react with another equivalent of tert-butyl isocyanide, followed by loss of a tert-butyl cation, ultimately affording the bis-iminonitrile product (9-2).

Although Xu proposed that their synthetic procedure does not involve radical intermediates, there are other studies on the silver-catalyzed (sp³)–H bond arylation of cyclic ethers proposing that radical intermediates may indeed form during the reaction mechanism. In 2021, Li et al. reported a novel protocol for the functionalization of cyclic ethers using heteroarenes via a Minisci-type reaction (Scheme ). In this protocol, a cross-dehydrogenative coupling between quinazolines and different cyclic ethers proceeds using AgOTFA (silver trifluoroacetate) and K₂S₂O₈ as a catalyst and oxidant, respectively. As one of the main limitations of this protocol, heteroarenes such as pyridine, quinoline (benzopyridine), or pyrimidine can be double functionalized. Therefore, to prevent this overfunctionalization, one of the potential positions (2 or 4) should be blocked by an appropriate substituent. It should be noted that even the most recent protocols for this transformation have not overcome this limitation, except by blocking the position 4 by a phenyl group in quinazoline substrates.

10. Amino Acid-Assisted Fluorination of Benzylic C­(sp³)–H Bonds.

To explain the reaction pathway, based on their findings and previous studies, the authors proposed that silver­(I) promotes the decomposition of K₂S₂O₈ to generate a sulfate radical intermediate. This radical abstracts a hydrogen atom from the cyclic ether substrate, leading to the formation of an ether radical (E), which subsequently adds to the protonated heteroarene (A) in a Minisci-type reaction to provide intermediate B. The radical cation B then loses two protons in consecutive steps to form the final arylated cyclic ether (10-3).

Radical or carbocation-based pathways are not the only protocols that have been offered during the past decade for the conversion of C­(sp³)–H bonds into C–C bonds. In 2022, Bi and colleagues reported a novel approach for silver-catalyzed benzylation of ethers using N-triftosylhydrazones safe and stable carbene precursors (Scheme ). In this protocol, a carbene pathway was exploited, as carbenes can be generated in situ from the bench-stable N-triftosylhydrazones. To demonstrate the flexibility of the method, the authors applied it to both intra- and intermolecular reactions, obtaining promising results. The broad substrate scope, high efficiency in gram-scale synthesis, and convenient regioselectivity in late-stage functionalization of complex molecules suggest that this protocol holds significant potential for further development and wider application.

11. Silver-Catalyzed Alkylation of Ethers.

To achieve mechanistic insight, the authors combined density functional theory (DFT) calculations with previous experimental and literature data. The results suggested that the reaction proceeds via in situ generation of a diazo compound from N-triftosylhydrazones, which forms a silver–carbene intermediate with the catalyst. This silver–carbene then undergoes a concerted C–H insertion with the ether substrate, consistent with prior observations from related silver-catalyzed C–H insertion reactions , and experimental evidence such as kinetic isotope effects (KIE) and ether coordination studies.

Unlike C–N bond formation, the current protocols for silver-catalyzed C­(sp³)–H to C–C bonds mostly rely on radical pathways and are governed by the innate reactivity of C–H bonds. Selectfluor, DDQ, and TBHP have been identified as effective oxidants for silver-catalyzed conversion of C­(sp³)–H to C–C bonds. So far, the main focus in this field has revolved around C–C bond formation itself, while stereoselective synthesis and reversed site-selective functionalization have remained unexplored. Therefore, further development is required to achieve site- and stereoselective synthetic protocols. Moreover, the activated C­(sp³)–H bonds employed so far are limited to benzylic, α-oxygen, and α-nitrogen sites, highlighting the need to expand silver-catalyzed alkylation chemistry to other classes of activated C­(sp³)–H bonds.

2.1.3. C–F Bond Formation

Fluorinated compounds represent an important class of molecules in pharmaceuticals, agrochemicals, and materials science. Over the past decade, C­(sp³)–H functionalization has been followed as a convenient and efficient strategy for fluorination. , For instance, Baxter’s group reported a protocol for the fluorination of methyl arenes using amino acids as radical precursors and AgNO₃ as the catalyst (Scheme ). The protocol was inspired by the well-known Strecker degradation, in which α-amino acids undergo decarboxylation to generate α-amino radicals. In this approach, α-amino radicals were exploited as HAT reagents for C­(sp³)–H fluorination. Since unprotected α-aminoalkyl radicals are typically sensitive to oxidation, this work represented the first successful example of employing them as synthetic intermediates. Selectfluor was chosen as the fluorine source because electrophilic fluorinating agents can serve as both oxidants and sources of atomic fluorine.

12. Amino Acid-Assisted Fluorination of Benzylic C­(sp³)–H Bonds.

As for the mechanism, the authors proposed that Ag­(I) coordinates with glycine to form an electron-rich silver species, which undergoes single-electron oxidation with Selectfluor to generate Ag­(II). The resulting Ag­(II) species promotes the decarboxylation of glycine, producing the corresponding amino radical (A). In fact, coordination of the amino acid to the silver center lowers the oxidation potential of Ag­(I), thereby facilitating oxidative decarboxylation under mild conditions. This amino radical then participates in a hydrogen atom transfer (HAT) process with the alkylbenzene substrate (12-1), generating a benzyl radical (B). Finally, the benzyl radical reacts with Selectfluor to yield the desired benzylic fluorinated product.

A few years later, silver-catalyzed fluorination of C­(sp³)–H bonds was further extended to heterogeneous catalysts by other groups. However, in 2019, Baxter’s team showed that this transformation can also proceed under homogeneous conditions without the need for amino acids. They demonstrated that pyridine ligands enable direct replacement of benzylic C–H bonds with fluorine. The crucial factor is the ability of simple pyridines to form [N–F–N]⁺ halogen bonds with Selectfluor, which promotes a single-electron reduction mediated by catalytic Ag­(I).

Although both Baxter’s studies were performed under mild conditions with acceptable yields, the methodology faces at least two major problems: (1) overfluorination and that inefficiency of the protocol for 3° benzylic C­(sp³)–H bonds. To address the second problem, Hamashima’s group disclosed a novel protocol employing amides as ligands and CsF as the fluorinating agent for the fluorination of C­(sp³)–H bonds (Scheme ). They observed that amide ligands such as benzamide and sulfonamide facilitate the conversion of alkyl aryl substrates via a carbocation pathway rather than through benzylic radical intermediates, as observed in Baxter’s work. This protocol is applicable to primary, secondary, and tertiary C­(sp³)–H bonds, and the screening results indicated that the presence of stabilizing substituents leads to higher yields, consistent with the proposed carbocation mechanism. However, this method also has drawbacks, including the formation of undesired side products such as alcohols and ketones.

13. Ag-Catalyzed Fluorination of Benzylic C­(sp³)–H Bonds Using Selectfluor as an Oxidant.

Similar to methods for the conversion of C­(sp³)–H to C–C bonds, published silver-catalyzed fluorination protocols have predominantly proceeded through the HAT process to generate carbon-centered radicals, which are subsequently functionalized either by direct radical capture with fluoride or via single-electron transfer (SET) to form a carbocation that can be intercepted by a fluoride anion. In terms of applicability, these protocols have been largely limited to the fluorination of methyl arenes, leaving other activated C­(sp³)–H bonds such as allylic, propargylic, and α-heteroatom sites largely unexplored. Furthermore, issues of site-, chemo-, and stereoselectivity remain essentially unaddressed in these transformations. In other words, the field requires the development of new silver-catalyzed fluorination strategies that enable selective and generalizable functionalization of targeted C–H bonds in a controlled manner.

2.1.4. C–O Bond Formation

Since C–O bonds are prevalent in a wide range of organic molecules, developing efficient methods to construct them directly from C–H bonds has long been of great interest to chemists. Although there are many published papers describing the catalytic oxygenation of C­(sp³)–H bonds, the number of papers that have used silver as a catalyst is very limited. This situation is the case for C–S bonds either, where there is only one work during the past decade in which silver acted as a mediator in the reaction pathway.

Silver has been shown to be an attractive candidate to convert C­(sp³)–H bonds into the corresponding C–O bond. As one example, in 2018, Tang and colleagues reported, for the first time, a protocol for the trifluoromethoxylation of benzylic C­(sp³)–H bonds using AgOTf and 1,10-phenanthroline-5,6-dione as the catalyst and ligand, respectively (Scheme ). Regarding the previous reports on trifluoromethoxylation reactions, , the authors selected trifluoromethyl arylsulfonate (TFMS) as the functionalization reagent. This protocol opened new opportunities for the synthesis of trifluoromethyl ethers, which are particularly attractive due to their high lipophilicity. To evaluate the scope of the reaction, a broad range of primary and secondary C­(sp³)–H substrates was screened. However, the regioselectivity of the method was not entirely satisfactory. Although it exclusively functionalizes primary C­(sp³)–H bonds in the presence of tertiary C­(sp³)–H bonds, competition between primary and secondary sites leads to the formation of product mixtures.

14. Silver-Catalyzed Trifluoromethoxylation of the Benzylic C­(sp³)–H Bond.

Based on the mechanism proposed by the authors and supported by DFT calculations, fluoride promotes the in situ conversion of AgOTf to Ag­(I)­F, which can be further oxidized to Ag­(II)­F₂ in the presence of potassium persulfate (K₂S₂O₈). The reaction between Ag­(II)­F₂ and TFMS generates F–Ag­(II)–OCF₃, which cleaves the benzylic C–H bond to produce the corresponding benzylic radical (A). Finally, A can follow two possible pathways: (a) direct reaction with F–Ag­(II)–OCF₃ to afford the corresponding product (14-3) or (b) further oxidation to form the related carbocation (B), which is subsequently trapped by OCF₃ ^– to yield the final product. Pathway (b) was supported by DFT calculations.

Very recently, Singh et al. described a silver-catalyzed, chemoselective oxidation of benzylic C­(sp³)–H bonds under mild conditions (Scheme ). Previous studies on silver-catalyzed benzylic oxidation had faced several drawbacks, such as the need for stoichiometric amounts of the catalyst, a limited substrate scope, and pronounced sensitivity to substituents on the starting materials. To overcome these issues, Singh and co-workers employed Ag^II(bipy)₂S₂O₈ as the catalyst in combination with Selectfluor as the oxidant, which delivered acceptable results with moderate yields. Nonetheless, the method proved ineffective for azabenzene substrates, including methylpyridines, methylpyridine N-oxides, and methylbenzimidazole. Mechanistically, the reaction follows a similar pathway to that reported by Tang, but the presence of water in this system converts the benzylic carbocations into the corresponding phenyl carbonyl compounds.

15. Silver-Catalyzed Benzylic Oxidation of C­(sp³)–H Bond.

These studies showed that over the past decade, silver-catalyzed oxygenation of C­(sp³)–H bonds has been restricted to the installation of −OCF₃ and carbonyl groups, affording the corresponding trifluoromethyl ethers and carbonyl compounds. However, other potential oxygenated products, including cyclic and acyclic ethers, alcohols, and esters, have remained unexplored. Mechanistically, current protocols rely almost exclusively on HAT and SET pathways, typically employing Selectfluor and K₂S₂O₈ as oxidants, while alternative strategies based on C–H activation or carbene/nitrene-type insertion have remained uncharted. These limitations highlight the need for new approaches that expand both the product’s scope and the mechanistic diversity of silver-catalyzed C–H oxygenation.

2.2. Unactivated C­(sp³)–H Bonds

Simple aliphatic C­(sp³)–H bonds without stabilizing groups exhibit high BDEs and are classified as unactivated C­(sp³)–H bonds. They can be categorized as follows: (1) C­(sp³)–H bonds with directing groups (typically heteroatoms that guide the catalyst/reagent to a specific C­(sp³)–H bond) and (2) C­(sp³)–H bonds without directing groups (Figure ). Functionalization of the latter is even more challenging, as such molecules lack “molecular handles” to distinguish between C­(sp³)–H bonds.

7.

Different types of unactivated C­(sp³)–H bonds.

2.2.1. Directed Functionalization

Directing groups, which can be categorized as nonremovable, removable, transient, or traceless, provide powerful tools to achieve selective functionalization of unactivated C–H bonds. By employing such groups, it is possible to discriminate among multiple C­(sp³)–H bonds with comparable reactivity within the same molecule. Literature review indicates that silver catalysts exhibit promising potential in directed C­(sp³)–H bond functionalization. In particular, several studies have demonstrated the ability of silver to promote remote C­(sp³)–H functionalization in the aliphatic chains of alcohols and amines. The key ideas in these reactions are based on the Hofmann–Löffler–Freytag (HLF) reaction where in its traditional version, a nitrogen radical intermediate grabs a hydrogen from distal C­(sp³)–H through a 1,5-HAT process, facilitating the functionalization reaction. Although this reaction originally was performed for amine compounds, the oxygen version has also developed.

Different transition metals have been reported for HLF-type reactions through a 1,5-HAT process, and silver is shown to have good potential to carry out this reaction. For instance, in 2018, Jiao’s group developed a protocol for the cyanoimination of remote C­(sp³)–H bonds in aliphatic alcohols in mild conditions (Scheme ). This protocol offered an opportunity to functionalize δ-C­(sp³)–H bonds without preactivation or manipulation of hydroxyl groups. Apart from moderate yields, one limitation of this study was revealed when the authors tested 2-methyl-1-butanol under the reaction condition, which led to a β-scission instead of direct C­(sp³)–H bonds. As another limitation of this work, the presence of a quaternary carbon in the alcohol chain inhibits the functionalization of the δ-C­(sp³)–H bond. In addition, no functionalization of terminal δ-C­(sp³)–H bonds has been observed.

16. Silver-Catalyzed Benzylation of Quinones.

Mechanistic studies showed that under the optimized condition, C­(sp³)–H bonds without a directing group including n-octane would not be functionalized showing the importance of the directing group in the reaction pathway. Also, adding radical scavengers such as TEMPO and butylated hydroxytoluene (BHT) prevent the reaction from producing the desired product. Regarding these results, the authors proposed that K₂S₂O₈ promotes the oxidation of Ag­(I) to Ag­(II), which is followed by the formation of a coordinated silver–alkoxide species (A). Homolytic cleavage of the Ag–O bond in A generates an alkoxide radical (B) along with Ag­(I). Subsequently, a 1,5-HAT process produces a radical intermediate C, which can be trapped by the cyanoimine unit (16-2), leading to intermediate D. Finally, D undergoes radical fragmentation to afford the corresponding δ-functionalized alcohol (16-3).

In 2021, two closely related and independent reports from Li’s and Hu’s groups described the functionalization of δ-C­(sp³)–H bonds in aliphatic alcohols using N-heterocyclic compounds. The differences between the two studies are only minor, such as the choice of acid (H₂SO₄ vs trifluoroacetic acid) and solvent (H₂O vs acetone/H₂O). Therefore, we discuss here in detail only the first report, namely, that from Li’s group (Scheme ).

17. Silver-Catalyzed Arylation of the C­(sp³)–H Bond.

Although Li’s protocol introduced heteroarenes as functionalization agents for δ-C­(sp³)–H bonds, the applicability of the method could not be extended to a broad range of substrates. According to the authors, quinolines bearing hydroxyl groups and five-membered heterocyclic compounds fail to undergo functionalization at the δ-C­(sp³)–H positions. Furthermore, only primary and secondary alcohols can be functionalized at δ-C­(sp³)–H bonds, whereas tertiary alcohols remain unreactive. Notably, these limitations observed for Li’s protocol were not encountered in Hu’s synthetic approach.

The authors carried out a series of reactions and proposed a plausible mechanism. In this pathway, Ag­(II), generated from the oxidation of Ag­(I) by K₂S₂O₈, first coordinates with the alcohol substrate to form a silver–alkoxide intermediate (A). Homolytic cleavage of the Ag–O bond releases Ag­(I) and produces the corresponding alkoxy radical (B). This radical then undergoes a 1,5-HAT process, affording the carbon radical (C). The N-heterocyclic compound salt subsequently traps this radical to give intermediate D, which undergoes dehydrogenation in the presence of a sulfate radical anion to furnish the final product (17-3).

Both Li et al.’s and Hu et al.’s reports on the functionalization of δ-C­(sp³)–H bonds in aliphatic alcohols require to be carried out under a nitrogen atmosphere. This drawback was recognized by other researchers, who sought ways to overcome it. Recently, a strategy has been introduced to achieve dehydrogenative coupling of unactivated C­(sp³)–H bonds in alcohols with quinazolines under ambient air. Besides replacing the inert atmosphere with air, the key improvement is the use of AgOTf as the catalyst instead of AgNO₃, which has proven to be more effective under aerobic conditions.

The literature shows that silver-catalyzed C­(sp³)–H functionalization using directing groups is not exclusively limited to Minisci-type reactions, where pyridine derivatives are employed to trap carbon radicals generated from C–H bonds. In 2022, Shen et al. developed a novel approach for the coupling of quinones or chromones with aliphatic alcohols as an example of C–H functionalization (Scheme ). They employed AgNO₃ as a catalyst and K₂S₂O₈ as an oxidant to functionalize δ-C­(sp³)–H bonds under mild conditions. Although the protocol was not successful for primary C–H bonds, it proved effective for secondary and tertiary C–H substrates, affording the corresponding products in moderate yields.

18. Alkenylation of Aliphatic Alcohols Using AgNO₃ as a Catalyst.

The reaction mechanism proposed by the authors shows some differences compared to the previously discussed ones. In previous mechanisms, the acidic environment protonated the N-heterocyclic compound, preparing it to trap the carbon radical intermediate. However, no acid is required in the present case, and the carbon radical (B) generated from the aliphatic alcohol radical (A) is directly trapped by the double bond of quinones or chromones leading to radical intermediate C. Subsequently, a sulfate ion removes the acidic hydrogen in C to yield the corresponding carbanion radical (D). Finally, Ag­(II)-assisted oxidation converts D into the final product (18-3).

Directed silver-catalyzed C­(sp³)–H functionalization protocols have proven effective for the alkylation of δ-C­(sp³)–H bonds. The key concept in these protocols relies on a 1,5-HAT process, in which an oxygen-centered radical abstracts a hydrogen atom from a δ-C­(sp³)–H bond through a six-membered cyclic transition state, generating the corresponding carbon-centered radical. However, current protocols face three major limitations: (1) they are restricted to the functionalization of alcohols, (2) C–C bond formation is the only reported outcome, and (3) the radical pathway remains the only developed approach in this field. Therefore, further research is needed to overcome these limitations by expanding the scope to other substrate classes, bond types, and mechanistic pathways.

2.2.2. IQNondirected Functionalization

Nondirected, catalyst-controlled C–H functionalization represents one of the most significant challenges in modern synthetic chemistry. Achieving selective functionalization of a specific C–H bond among multiple sites with comparable reactivities is often regarded as the ultimate goal in this field. As a result, selective functionalization of these bonds has traditionally relied on their innate chemical reactivity. However, a new trend is emerging in which catalyst/ligand design plays the dominant role in discriminating between these bonds.

Literature review shows that there are three classes of reactions that have been promoted using silver-catalyzed functionalization of unactivated C–H bonds during the past decade, namely, chlorination, amination, and alkylation. For example, In 2017, Kanai and Ozawa reported a silver-catalyzed chlorination using Ag­(phen)₂OTf as the catalyst and tert-butyl hypochlorite (^tBuOCl) as the chlorine source (Scheme ). The reaction proceeded smoothly at room temperature under an air atmosphere, which represents a notable advantage. However, several limitations should be noted. The reaction generally afforded only moderate yields, the selectivity between similar γ- and δ-C–H positions was unsatisfactory, and the method was unsuitable for aliphatic primary C–H bonds. Indeed, the authors reported successful chlorination only for benzylic, tertiary, and secondary C–H bonds. In addition, the protocol showed poor tolerance toward certain functional groups such as CC and CC bonds, and in some amine substrates, oxidation of the amine interfered with the reaction pathway.

19. Chlorination of Benzylic C­(sp³)–H Bonds Using AgOTf as a Catalyst.

To interpret the reaction pathway, the authors suggested a plausible mechanism in which ^tBuOCl reacts with Ag­(phen)₂OTf to produce a dinuclear silver­(II) complex (A). Homolytic cleavage of this dinuclear complex generates a t-butoxy radical, which abstracts a hydrogen atom from the substrate (19-1) to give the radical intermediate B. The latter then reacts with chlorine to afford the corresponding chlorinated product (19-2) along with Ag­(I). Alternatively, the reaction may proceed via pathway B, in which the dinuclear complex A is converted into intermediate C. This intermediate can subsequently furnish the final product through an intramolecular chlorination process.

Silver-catalyzed conversion of an unactivated C–H bond to a C–N bond is another target that has been pursued by chemists during the past decade. In 2017, Schomaker’s group reported that it is possible to achieve a selective amination between two 3 °C­(sp³)–H bonds with similar steric and electronic environments via changing the nature of an N-donor ligand for the Ag­(I) complex. However, there were still limitations to extend the protocol for a wide range of substrates, and the authors used other complexes, including rhodium, to achieve desirable site selectivity. Recently, the same group conducted computational studies to gain a better understanding of the regioselectivity of the reaction and concluded that both the ancillary ligand and the identity of the nitrene precursor influence the transition state geometries, leading to C–H amination at different sites.

As another example of nondirected C­(sp³)–H bond amination, Cao et al. recently reported a protocol for the site-selective amination of secondary over primary C­(sp³)–H bonds using AgClO₄ as the catalyst (Scheme ). The observed site selectivity was 15:1, which increased to 20:1 when substrates containing activated secondary C­(sp³)–H bonds, such as methylene ethers, were employed. Notably, although the protocol enabled the amination of propargylic C­(sp³)–H bonds, it failed to promote the amination of allylic C­(sp³)–H bonds. The proposed mechanism was consistent with previous reports on silver-catalyzed C­(sp³)–H bond amination via nitrene transfer.

20. Synthesis of Cyclic Sulfamates via C­(sp³)–H Bond Amination.

Besides chlorination and amination, alkylation of unactivated C­(sp³)–H bonds using silver catalysts has been followed by chemists during the past decade. At least two related papers have covered this field. For example, in 2022, Pérez and co-workers introduced a silver-catalyzed alkylation of linear alkanes (pentane and hexane) via carbene transfer using diazoacetates as functionalization agents (Scheme ). Until then, regioselective C­(sp³)–H bond functionalization using diazo compounds had been limited to Rh-based catalysts. − However, this report extended the protocol to silver complexes. The authors observed that unlike Rh-based systems, in which the catalyst governs selectivity, here, the diazo compound was the main factor determining the site selectivity. Specifically, donor–acceptor carbenes (derived from aryl diazoacetates) favored functionalization at secondary sites, whereas acceptor carbenes (from ethyl diazoacetate) preferentially targeted primary (terminal) C–H bonds. These results contrasted with those reported for rhodium catalysts, where the same diazo compounds led to different site selectivities.

21. Silver-Catalyzed Alkylation of Alkanes Using Diazo Compounds.

The same group performed a combined computational and experimental study to gain further insight into the reaction mechanism of silver-catalyzed functionalization of alkanes via carbene intermediates derived from diazo compounds. DFT calculations revealed that there was no barrier in the potential energy surface for C–H bond activation and that primary C–H bonds were functionalized more selectively than secondary ones. The authors attributed this outcome to the higher probability of a methyl group approaching the carbene center compared to a methylene group.

Recently, Bi et al. disclosed a novel site-selective alkylation of alkanes using bench-stable vinyl-N-triftosylhydrazones as functionalization agents (Scheme ). This protocol represented the first instance of using a nonacceptor alkenyl carbene as the functionalization agent for alkane C­(sp³)–H bonds, which selectively targeted tertiary C­(sp³)–H bonds over secondary and primary ones. An important side reaction was cyclopropanation, and the authors found, based on a series of experimental and computational studies, that this undesired pathway could be suppressed by employing a large excess of the alkane substrate.

22. Silver-Catalyzed Allylation of C­(sp³)–H Bonds.

Achievements in silver-catalyzed functionalization of unactivated C­(sp³)–H bonds can be broadly classified into two mechanistic categories: (1) radical pathways and (2) nitrene- or carbene-based mechanisms. Protocols that proceed through radical intermediates typically employ ^tBuOCl as a radical initiator, which reacts with the silver catalyst to generate ^tBuO• radicals via homolytic cleavage. However, this strategy has shown that the outcome does not necessarily correlate with bond dissociation energy (BDE) trends. For example, based on BDE considerations, homolytic cleavage of α-C–H bonds adjacent to oxygen or carbonyl groups would be expected to be favored over secondary C­(sp³)–H bonds, yet the opposite preference was observed. By contrast, protocols involving nitrene or carbene intermediates demonstrate greater tunability. In these protocols, site selectivity can be modulated by altering the ligand environment or by changing the nature of the carbene/nitrene precursor itself. These insights highlight the potential of nitrene- and carbene-based strategies to overcome the intrinsic limitations of radical pathways in silver-catalyzed C–H functionalization.

3. Conclusions and Outlook

Silver catalysis has established itself as a powerful yet underexplored tool for C­(sp³)–H functionalization. Significant progress has been made in developing protocols for C–N, C–C, C–O, and C–X bond formation, with ligand design emerging as a decisive factor for chemo-, site-, and stereoselective functionalization. Despite these achievements, the field still faces fundamental challenges: unactivated C­(sp³)–H bonds remain difficult to target, stereoselective protocols are rare, and oxygenation and halogenation strategies lack mechanistic diversity.

Looking forward, several directions appear particularly promising. First, the integration of silver catalysis with photoredox or dual catalytic systems could provide access to reactivity patterns unattainable under traditional conditions. Second, computational modeling and data-driven ligand design may accelerate the discovery of selective catalysts capable of overriding innate bond reactivities. Third, expanding the chemistry beyond model substrates to pharmaceuticals, natural products, and functional materials will be essential for demonstrating real-world applicability. Finally, adopting greener oxidants and sustainable conditions will enhance both environmental and industrial relevance. Taken together, these efforts will help establish silver catalysis as a mature and versatile platform, competitive with Rh, Ru, and Cu systems, for late-stage C­(sp³)–H bond functionalization in modern synthetic chemistry.

No new data were generated or analyzed in support of this study.

The author declares no competing financial interest.