Three-component, stereoselective C–N bond forming alkene difunctionalization

Abstract

Amines are essential functional groups in pharmaceuticals, agrochemicals, and bioactive molecules, with C(sp³)–N bonds playing a crucial role in enhancing biological activity and selectivity. Alkene difunctionalization offers a powerful strategy for constructing these bonds by introducing two distinct functional groups across a double bond in a single step. While two-component alkene difunctionalization has been widely studied, general three-component strategies for amine synthesis remain underdeveloped due to challenges in controlling regioselectivity, stereoselectivity, and competing side reactions. Recent advancements have addressed these limitations through transition-metal catalysis, directing-group-free methodologies, and radical-based mechanisms, enabling stereoselective synthesis of amines from readily available starting materials. This review discusses emerging strategies in three-component, stereoselective C–N bond-forming alkene difunctionalization, emphasizing mechanistic innovations and their impact on synthetic organic chemistry.

---

Introduction

Amines are essential functional groups in a broad range of bioactive compounds, playing pivotal roles in pharmaceuticals, agrochemicals, and other organic molecules. Their significance is underscored by their fundamental presence in numerous pharmaceutical drugs (Fig. 1). Among these, amines containing C(sp³)–N bonds are particularly noteworthy due to their three-dimensional structures, which enhance biological activity, metabolic stability, and selectivity in drug molecules. As a result, the efficient and selective construction of C(sp³)–N bonds is a critical step in synthesizing these molecules, and substantial effort has been directed toward advancing strategies for the selective synthesis of amines with C(sp³)–N bonds.^1–4

Fig. 1 Representative examples of pharmaceuticals containing C(sp³)–N bond.

Alkene difunctionalization is a powerful synthetic strategy that introduces two distinct functional groups across a double bond in a single step, enabling rapid molecular complexity expansion from readily available starting materials.^5–7

While alkene difunctionalization involving two reaction components has been extensively explored, these reactions typically rely on alkenes with tethered amine nucleophiles, leading to the formation of cyclic heteroarenes, or on the ambiphilic activation of specialized coupling partners (Fig. 2A). In contrast, more general three-component alkene difunctionalization for the synthesis of amines remains a relatively underexplored area (Fig. 2B).

Fig. 2 Two-component and three-component alkene difuctionalization for the synthesis of amines.

The primary challenge in developing such three-component alkene difunctionalization reactions lies in preventing the formation of undesired side products. In such multi-component systems, it is exceptionally difficult to control competing reaction pathways while achieving the desired reactivity. Moreover, achieving high levels of regioselectivity, diastereoselectivity, enantioselectivity, and site selectivity adds further complexity (Fig. 2C). Despite these difficulties, overcoming these challenges would enable a modular and versatile approach to synthesizing structurally diverse amines containing C(sp³)–N bonds from simple and readily available chemical building blocks.

Recently, significant progress has been achieved in this field through the development of complementary strategies (Fig. 3). One approach involves the incorporation of specific functional groups at the termini of alkene substrates, which coordinate with transition-metal catalysts (Fig. 3A). These functional groups serve as directing groups, guiding the transition-metal catalyst to activate the alkene and selectively form a new bond at a specific position. Various directing groups, such as aminoquinoline, have been successfully utilized. Recent advancements have further expanded the use of native functional groups, such as alcohols and amines, as directing groups in palladium- and nickel-catalyzed reactions.

Fig. 3 Three-component strategies for the stereoselective synthesis of amines.

Alternatively, considerable efforts have been dedicated to developing reaction systems that eliminate the need for a directing group (Fig. 3B). This strategy is advantageous as it avoids additional synthetic steps required to install and remove directing functionalities when they are not part of the target molecule. Notably, recent advances in Rh(III)-catalysis have enabled “directing-group-free” alkene difunctionalization, facilitating the stereoselective synthesis of amine products. In these systems, ligands on Rh play a crucial role in achieving regio-, diastereo-, and site-selective transformations, allowing for the three-component synthesis of acyclic amines from a variety of alkene starting materials.

Another promising strategy leverages the unique reactivity of radical mechanisms (Fig. 3C). In this approach, radical intermediates, generated via photochemical or electrochemical methods, add to the π-bond of an alkene to form carbon-centered radicals. Subsequent reaction with a second component yields the desired difunctionalized product. While the formation of sp²-hybridized carbon radicals can lead to the loss of stereochemical information from the starting alkene, the stability of the intermediate radical, combined with its capture by a transition-metal catalyst and the subsequent formation of a new σ-bond, enables stereoselective synthesis of acyclic amine products.

These strategies complement each other by addressing challenges in reaction scope and selectivity. Directing-group-assisted methods offer high regio- and stereoselectivity but require pre-functionalized alkenes, while directing-group-free approaches simplify synthesis yet often struggle with substrate scope and regioselectivity. Both typically rely on transition-metal catalysis, where syn-migratory insertion can enhance diastereoselectivity. In contrast, radical-based strategies enable diverse bond formation via photochemical or electrochemical activation but often face challenges in stereocontrol due to the formation of carbon-centered radicals. Together, these approaches enhance the versatility of three-component alkene difunctionalization for amine synthesis.

While several reviews have explored alkene difunctionalization,^8–14 they often focus on specific aspects that do not fully encompass the scope of this work. Here, we provide a comprehensive review of three-component, transition-metal-catalyzed stereoselective synthesis of acyclic amines from alkenes. Emphasizing recent advancements, we highlight mechanistic strategies that enable various forms of stereoselectivity in C–N bond-forming alkene difunctionalization, offering new insights into this evolving area of synthetic methodology.

Directing group-free Rh catalysis

Rh(III)-Catalyzed carboamidation of alkenes

Carboamination of alkenes enables the simultaneous formation of C–N and C–C bonds in a single step, producing valuable nitrogen-containing molecules while extending the carbon framework of the molecule. In 2015, the Rovis group reported the first example of Rh(III)-catalyzed, syn-carboamination of alkenes using N-enoxyphthalimides.¹⁵ This reaction was notable as the first diastereoselective (syn-selective), intermolecular carboamination of alkenes that produced acyclic products. However, it relied on N-enoxyphthalimides as both the carbon and nitrogen sources, a specialized reagent requiring multi-step synthesis and limited derivatization potential.

To address these limitations, the Rovis group developed a three-component carboamination reaction that utilized simple and readily available carbon and nitrogen coupling partners. In this reaction, aryl boronic acids served as the carbon source, while dioxazolones—readily synthesized from carboxylic acids—acted as the nitrogen source (Fig. 4).¹⁶

Fig. 4 The selected substrate scope of Rh-catalyzed three-component carboamination of alkene.

During reaction development, the authors faced several challenges, including the formation of undesired side products. The occurrence of two-component C–N coupling byproducts was mitigated by employing electron-deficient alkene coupling partners that promote alkene migratory insertion. Additionally, hydroarylation and Heck-type side products, arising from protodemetalation or β-hydride elimination after migratory insertion, were minimized by using a more reactive nitrene precursor, dioxazolone. Further optimization of solvents, temperature, and additives ultimately led to reaction conditions that achieved the desired carboamination product (4d) in 68% yield using catalytic amounts of [Cp*RhCl₂]₂, phenylboronic acid as the carbon source, 3-methyl-1,4,2-dioxazol-5-one as the nitrogen source, and benzyl acrylate as the alkene substrate in methanol at room temperature.

Notably, this reaction does not require a directing group, yet it still gives the desired carbonamination products with complete regioselectivity when electronically activated alkene coupling partners are used.

As a reaction scope of the reaction, various arylboronic acids can be used for the reaction, forming the corresponding carboamination products (4a, 4b, 4d). Alkylboronic acids failed to give the products.

Electron-deficient alkenes such as acrylates, and secondary acrylamides (4c) can be used for the reaction, which generates α-amino acid derivatives as products. Particularly, the reaction with internal cyclic alkenes such as norbornene (4e) oxabenzonorbornadiene (4f), or cyclopropene (4h) gives excellent, syn-diastereoselectivity. However, the reactions with unactivated alkenes or styrenes failed to deliver the desired three-component product.

As a proposed mechanism (Fig. 5), first, Rh catalyst undergoes transmetalation with arylboronic acid to give Rh–aryl complex (5). Next, turnover limiting migratory insertion into the Rh–aryl bond forms Rh intermediate (6). Subsequently, dioxazolone coordinates to the electron-rich alkyl Rh(III) complex, followed by Rh–nitrene formation with the exclusion of CO₂. The desired syn-carboamination product (8) is formed after reductive elimination and proto-demetalation.

Fig. 5 Proposed mechanism of three-component, Rh(III)-catalyzed syn-carboamination of alkenes.

The relative stereochemistry of the reaction was determined by the reaction with a monodeuterated benzyl acrylate, which confirmed the syn-carboamination of the alkene. The authors rationalize that Rh intermediate (6) undergoes facile C–N bond formation faster than O-bound Rh–enolate (9) formation, which can lead to anti-carboamination product 11.

Inspired by the fact that reactions with acrylamide as the alkene coupling partner yield products containing two amide bonds (e.g., 4c), the authors demonstrated the applicability of this method to peptide synthesis. Specifically, a reaction involving dioxazolone (prepared by modifying the carboxylic acid of one amino acid) and acrylamide (synthesized through acylation of another amino acid) produced a tripeptide, forming a new amino acid residue in the process, albeit low yield and diastereoselectivity.

In 2023, the Rovis group reported an improved reaction system for peptide ligation via selective three-component carboamidation. This method utilized Rh(III) catalysis to couple dioxazolones, acrylamides, and arylboronic acids, offering an effective and unique disconnection strategy for peptide synthesis (Fig. 6).¹⁷

Fig. 6 The effect of ligand, observed side products and selected reaction scope of synthesis of unnatural peptides via Rh(III)-catalyzed diastereoselective three-component carboamidation.

While utilizing previous reaction conditions⁹ delivered the product with Phth–Gly–Tyr–Val–OEt tripeptide sequence (15a) in 32% yield with 1 : 1.8 dr (diastereoselectivity) (D : L), with the generation of undesired side products resulted from β-hydride elimination (15h), hydroamination (15i), and direct C–N coupling (15j).

The authors found that replacing the pentamethylcyclopentadienyl (Cp*) ligand on Rh(III) catalyst to tetramethylcyclopentadienyl (Cp^TM) causes an inversion of stereoselectivity to 2.4 : 1 dr (D : L) with a slight increase in reaction yield (41%). Cp^3Me (trimethylcyclopentadienyl) gave similar diastereoselectivity, but significantly lower yield (18%, 3.2 : 1 dr). Changing solvent from methanol to DMF significantly improved the reaction yield, delivering 84% yield, and 3.4 : 1 dr (D : L) of the desired product (15a).

Unlike conventional peptide synthesis, this method offers a complementary and modular disconnection strategy in which readily available arylboronic acids act as a bridge between two peptides while simultaneously installing an unnatural amino acid residue within the peptide chain. Peptides incorporating residues beyond the 20 natural amino acids—such as those with D-stereocenters or β-amino groups—often exhibit enhanced enzyme affinity, making them highly valuable for pharmaceutical discovery.¹⁸

While solid-phase peptide synthesis, biological protein translation machinery, and transition-metal-catalyzed selective protein modifications (particularly using Pd- or Rh-based catalysis) remain the predominant methods for synthesizing peptide chains containing unnatural amino acid residues,^19–23 this approach offers a practical alternative. Unlike conventional methods that rely on individual unnatural amino acids—which can be expensive or commercially unavailable—or the post-synthetic modification of peptide chains, this strategy utilizes readily available arylboronic acids to efficiently introduce such residues.

The reaction demonstrates the broad scope and high functional group tolerance, as evidenced by 52 examples, including a carfilzomib analog (15b), a proteasome inhibitor approved by the FDA for multiple myeloma treatment.²⁴

Notably, two large 10-mer oligopeptide components successfully reacted with 4-formylphenylboronic acid, in the presence of Rh catalyst, bridging the two peptides to synthesize a 21-mer polypeptide containing an unnatural amino acid residue (15g). This example underscores the excellent chemoselectivity and functional group tolerance of the method, as the Rh catalyst precisely recognizes and reacts with the desired functionalities of each coupling partner, even in the presence of numerous other functional groups.

The mechanism of the transformation (Fig. 7) parallels that found in their original carboamidation report.¹⁶ Arylboronic acid undergoes transmetalation with the active Rh catalyst (II), forming a Rh–aryl complex (III). The acrylamide substrate then coordinates to this complex, followed by a 1,2-migratory insertion step that forms a C–C bond. This step, regulated by the adjacent residue of the acryloyl moiety, is presumed to be both the irreversible rate-determining and regioselectivity-determining step.

Fig. 7 Proposed reaction mechanism of peptide ligation for three-component carboamination by Rh(III)-catalysis.

The Cp^TM ligand plays a crucial role in controlling diastereoselectivity by accommodating the preferred C–N bond rotamer in the s-cis conformation, allowing the Rh(III)–Ar species to approach from the sterically less hindered face. Additionally, Cp^TM provides an optimal electronic environment, balancing between the electron-rich Cp* and the electron-deficient Cp^3Me, thereby minimizing side reactions and enhancing the yield of the desired three-component product.^25,26 Subsequently, dioxazolone coordinates to the Rh(III) complex, generating a Rh(III)–nitrene species (VI) with CO₂ release. The C–N bond is formed through 1,1-migratory insertion of the Rh–enolate bond with stereoretention. The peptide product is released via protodemetalation, and the Rh catalyst is regenerated to its active Rh(III) form.

Following the successful demonstration of linear peptide synthesis, the authors reported a Rh(III)-catalyzed macrocyclization through the carboamidation of acryloyl–peptide–dioxazolone precursors (Fig. 8).²⁷ This method features a versatile reaction scope and high diastereoselectivity, with some examples achieving isolated diastereomeric ratios exceeding 20 : 1.

Fig. 8 The reaction scope of Rh(III)-catalyzed carboamidation for the synthesis of unnatural peptide macrocycles.

As a practical application, this peptide macrocyclization strategy was employed to synthesize cyclosomatostatin (18e), a somatostatin receptor antagonist, and gramicidin S (18f), an antimicrobial agent. To improve substrate solubility, a co-solvent system comprising ethylene glycol and DMF in a 1 : 1 ratio was utilized, resulting in an overall isolated yield of 40% with >20 : 1 dr for both compounds. Additionally, this approach enabled the synthesis of macrocyclic peptides from 14-mer peptides and aryl boronic acids to produce 15-mer macrocyclic peptides, yielding 32% with an isolated diastereoselectivity of 7.0 : 1 (18g). Similar to previous peptide ligation, the reaction competes with β-hydride elimination resulting in Heck byproduct.

Rh(III)-Catalyzed 3,4-difunctionalization of 1,3-dienes

β-Amino alcohols are prevalent motifs in various fields, including pharmaceuticals and agrochemicals. One effective method to access this structural motif is through the oxyamination of alkenes. While classical Os-catalyzed oxyaminations of α-olefins and cyclic alkenes are well-established, site-selective oxidation of the two reactive alkenes in conjugated 1,3-dienes remains a significant challenge. For internal dienes, site-selective oxyamination can be achieved using a carbamate directing group in combination with Rh(II) carboxylates. However, in the case of terminal dienes, although 1,2- and 1,4-functionalizations are well-studied, 3,4-amino oxygenation of 1,3-dienes remains unexplored.

In 2021, the Rovis group reported a Rh(III)-catalyzed three-component, highly diastereoselective amino oxygenation of 1,3-dienes. This method utilized readily available dioxazolones as the nitrogen source and alcohols, which also served as the solvent, as the oxygen source (Fig. 9).²⁸

Fig. 9 Rh(III)-Catalyzed, three-component 3,4-amino oxygenation of 1,3-dienes.

Through extensive evaluation of Rh catalysts and reaction conditions, the authors discovered that the cationic Ind*Rh(III) catalyst, generated in situ by combining the [Ind*RhCl₂]₂ complex with AgSbF₆, delivered the desired oxyamination product (22a) from 4-phenyl-1,3-butadiene with a high yield (62%) and excellent diastereoselectivity (17 : 1).

Conventional Cp* ligand (Rh-1) and trimethylindenyl (Rh-2) provided trace amount of products while [Ind*RhCl₂]₂ catalyst (Rh-3) produced the desired product with improved yield and improved diastereoselectivity was observed with cationic [Ind*Rh(MeCN)₃](SbF₆)₂ catalyst (Rh-4) (Fig. 9A). Based on these results, the authors evaluated various Ag salts that can generate cationic Rh(III) catalysts and identified the combination of [Ind*RhCl₂]₂ dimer and AgSbF₆ provides the best results.

This methodology demonstrated broad applicability, accommodating a range of 4-aryl and 4-alkyl-1,3-butadienes, dioxazolones, and alcohols to produce the corresponding amino oxygenation products in good yields and diastereoselectivities. Notably, most of the reactions exclusively afforded 3,4-difunctionalized products.

To explain the observed high diastereoselectivity, the authors conducted a series of experimental studies and proposed a stereochemical model (Fig. 10). They suggested that the Ag(I) salt facilitates the formation of a cationic Rh catalyst, which coordinates with the 1,3-diene. The alcohol then undergoes an anti-selective nucleophilic attack, generating a key π–allyl intermediate (24). In the presence of the silver salt, dioxazolone coordination is accelerated, enabling subsequent oxidation of the Rh center via N–O bond cleavage of the dioxazolone (20). This is followed by migratory insertion and protodemetallation, ultimately yielding the desired diastereomer (25).

Fig. 10 Proposed mechanism of Rh(III)-catalyzed selective oxyamination using alcohols.

In contrast, in the absence of the silver salt, the π–allyl complex (24) can undergo migration along the allyl moiety, accompanied by single-bond rotation. This process leads to the unselective formation of both diastereomers (25 and 28).

One limitation of this study was the use of simple alcohols as oxygen sources in solvent quantities. To address this, the authors expanded the nucleophile scope of their previous reaction system, enabling the use of synthetically viable quantities (3–10 equiv.) of general nucleophiles, including water, alcohols, and amines, by employing HFIP as the solvent and switching silver salt to AgBF₄ (Fig. 11).²⁹ The choice of ligand on Rh(III) catalyst ([Ind*RhCl₂]₂, Rh-3) was crucial to achieve high yield and diastereoselectivity as the commonly used pentamethylcyclopentadienyl Rh(III) complex ([Cp*RhCl₂]₂, Rh-1) produces only trace amounts of the desired product. The modified [Cp^tRhCl₂]₂ (Rh-5) catalyst, which shares similar electronic and steric properties with the [Ind*RhCl₂]₂ complex,^25,26 was the only other catalyst to deliver a significant yield of product. When 1,3-dienes contain nucleophilic functional groups such as alcohols, amines, or carboxylic acids, intramolecular cyclization yields lactones, morpholines, pyrrolidines, and piperidines in good yields. Notably, unprotected alcohols (32b–e) can be directly synthesized using water as the nucleophile, providing a cost-effective and straightforward approach to accessing amino alcohols. Carboxylic acids, however, react exclusively intramolecularly, likely due to carboxylates acting as bidentate ligands, preventing 1,3-diene coordination to Rh complexes. A broad range of unactivated 1,3-dienes and dioxazolones serve as effective substrates, delivering 3,4-difunctionalized products with high yields and diastereoselectivities.

Fig. 11 Scopes of Rh(III)-catalyzed selective difunctionalization of dienes using various nucleophiles.

Anti-Markovnikov hydroamidation of unactivated alkenes

In 2022, Rovis group introduced an innovative method for Rh(III)-catalyzed anti-Markovnikov hydroamidation of unactivated alkenes, employing dioxazolones as amidating agents of the reaction (Fig. 12).³⁰ This approach uses environmentally friendly isopropanol as a hydride source. The Rh(III)–hydride generated the reaction with isopropanol, which was used as cosolvent of the reaction, inserts into an alkene, followed by trapping with a dioxazolone, which would lead to anti-Markovnikov hydroamidation products. The authors found the reaction conditions that deliver a high yield of the desired hydroamidation product with excellent regioselectivity. Especially the Rh(III) catalyst with electron-deficient 1,2,3,4-tetramethyl-5-trifluoromethylcyclopenta-1,3-dienyl (Rh-6) was crucial to achieve high yield since the catalyst with prototypical pentamethylcyclopentadienyl (Cp*) ligand (Rh-1) gave much lower yield. It is presumed that increased electron deficiency of the catalyst may aid migratory insertion into the alkene, resulting in higher reactivity.

Fig. 12 Rh(III)-Catalyzed anti-Markovnikov hydroamidation of unactivated alkenes.

A wide range of functionalized alkenes, including free and protected alcohols, amines, nitriles, sulfones, and epoxides, are compatible with the hydroamidation reaction. Notably, ketones remain intact even under reducing conditions, and complex natural products such as linalool and sclareol undergo hydroamidation efficiently.

The reaction also tolerates sterically hindered substrates, though increased bulk leads to lower yields and higher diastereoselectivity, as seen with β-pinene and (+)-longifolene. Beyond acetamide installation, diverse amides, including those derived from N-phthaloyl glycine and dehydrocholic acid, were successfully incorporated using various dioxazolones. Additionally, the method is effective for styrenes and electron-deficient alkenes, and terminal amidation can be achieved via alkene isomerization in select cases.

After extensive mechanistic investigation, they proposed a mechanism (Fig. 13) that starts with the formation of Rh alkoxide (II) from isopropanol facilitated by K₂CO₃. It then undergoes β-hydride elimination to generate Rh hydride (III) and release acetone. Coordination of the alkene leads to intermediate (IV), which undergoes reversible migratory insertion, forming either alkylrhodium species (V) or (Va). Since only the linear product is observed, it is inferred that only (V) proceeds to amidation, while (Va) undergoes β-hydride elimination, reverting to (IV). This was supported by deuterium labelling experiments with terminally deuterated 1-undecene-d₂ that showed some of the deuterium incorporation at C1 is transferred to C2. The high terminal selectivity for amidation therefore suggests a higher barrier to amidation for the secondary alkylrhodium species (Va). Coordination of dioxazolone to (V) forms intermediate (VI), followed by turnover-limiting N–O bond cleavage and CO₂ extrusion, yielding a Rh nitrenoid species (VII). Subsequent migratory insertion and protodemetalation release the hydroamidated product and regenerate the active catalyst.

Fig. 13 Proposed mechanism.

During the substrate scope study, the authors observed low yields of terminal amidation products with two internal alkenes, suggesting a chain-walking mechanism. This observation led them to hypothesize that undirected remote hydroamidation of internal alkenes could be achieved. During the optimization study, they found that switching base from K₂CO₃ to DIBNBA (diisobutyl-n-butylamine) was crucial to obtaining high yield since K₂CO₃ caused the catalyst inhibition. After further optimization of the reaction conditions, they developed Rh(III)-catalyzed remote hydroamidation of internal alkenes via chain walking (Fig. 14).³¹

Fig. 14 The selected substrate scope of Rh(III)-catalyzed remote hydroamidation of internal alkenes via chain walking.

A wide range of functional groups on both the alkene and dioxazolone partners were well tolerated, affording the corresponding products with amides selectively installed at the terminal position. Notably, the conversion of alkene isomer mixtures into a single amide product highlights the method's potential for regioconvergent synthesis, demonstrating its broad synthetic utility.

Directing group-assisted approaches

Pd-Catalysis

Another useful strategy for achieving three-component alkene difunctionalization for the synthesis of amines is using a directing group. In 2016, the Engle group reported a Pd-catalyzed, regioselective hydroamination method using a removable 8-aminoquinoline directing group.³²

Although hydroamination is a highly atom-efficient reaction with significant synthetic potential, existing methods suffered from limitations including harsh reaction conditions, poor chemo-, regio-, and stereoselectivity, and limited alkene and nitrogen nucleophile scope.^33–39 For example, the Wacker process involves a key nucleopalladation step that generates an alkyl palladium(II) intermediate, which subsequently undergoes β-hydride elimination to yield the oxidized alkene product (Fig. 15A).^40,41 However, reactions with unactivated alkenes present significant challenges in both reactivity and site selectivity.^42,43 To address this, the authors envisioned intercepting the aza-Wacker aminopalladation intermediate via protonation to afford the hydroamination product.

Fig. 15 Directing group-assisted approaches for hydroamination of unactivated alkenes.

A removable bidentate directing group, 8-aminoquinoline, was employed to achieve regioselectivity and stabilize the palladium intermediate (Fig. 15B). This directing group not only guides the regioselective nucleophilic addition but also prevents β-hydride elimination, prolonging the lifetime of the aminopalladation intermediate and enabling protodepalladation. This strategy enables the selective synthesis of highly functionalized γ-amino acids with excellent regioselectivity.

This method reacts well with a wide range of nitrogen nucleophiles (Fig. 16), including phthalimides (46a), Boc-protected amines (46b), and hydroxamic acids (46c, 46e). Electron-deficient azaheterocycles and other nucleophiles are also reactive, suggesting a wide range of synthetic possibilities. For the alkene substrate scope, a diverse range of unactivated terminal alkenes underwent anti-Markovnikov hydroamination, affording good to excellent yields. Notably, sterically hindered α,α-disubstituted alkenes also reacted successfully (56d), albeit requiring increased palladium loading and concentration. The reaction also demonstrated excellent functional group tolerance. This transformation proved effective for unactivated internal alkenes under slightly modified conditions, requiring higher Pd loading (10 mol%) and 4-methoxybenzoic acid instead of benzoic acid. As expected, both trans- and cis-3-hexenoic acids (46f, 46g) yielded the same hydroaminated product.

Fig. 16 The reaction scope.

To investigate the aminopalladation mechanism, the authors examined a cis-locked cyclohexyl olefin and observed that succinimide addition occurred trans to the directing group (46h). Based on the assumption that palladium coordinates to the same face of the alkene as the directing group, they proposed an anti-aminopalladation pathway via an outer-sphere attack.

As a proposed catalytic cycle (Fig. 17), the palladium(II) catalyst first coordinates with the directing group, positioning it near the olefin and facilitating π-Lewis acid activation. Subsequently, nucleopalladation occurs, which proceeds via an outer-sphere mechanism, yielding the trans-nucleopalladated intermediate. Due to the structural stability and rigidity provided by the directing group, the palladacycle avoids β-hydride elimination, instead persisting long enough to undergo protodepalladation. This final step releases the hydroaminated product while regenerating the active palladium catalyst.

Fig. 17 Proposed catalytic cycle.

Building on the successful demonstration of hydroamination, the Engle group reported carboamination of unactivated alkenes (Fig. 18).⁴⁴ Carboamination of alkenes has been studied in various ways to synthesize structurally complex amines from relatively common and inexpensive starting materials. However, achieving three-component, catalytic intermolecular carboamination of unactivated alkenes has remained a significant challenge. While previous studies have mainly relied on immobilized nucleophiles or activated alkene substrates, this work builds on previous successes in Pd(II)-catalyzed alkene hydroamination to investigate whether chelation-stabilized aminopalladated intermediates can be intercepted by carbon electrophiles such as aryl or alkenyl iodides.

Fig. 18 Pd(II)-Catalyzed three-component carboamination of alkenes.

After the optimization study, the authors found the reaction conditions that give 85% of the desired carboamination product (60a), using 3-butenoic acid, masked as the corresponding 8-aminoquinoline (AQ) amide, as alkene substrate, phthalimide as nitrogen nucleophile, styrenyl iodide as carbon nucleophile in HFIP in the presence of Pd(OAc)₂ catalyst and base.

The reactions in other solvents such as toluene, MeCN, DCE gave significantly lower yield (<34%). Further optimization showed that higher reaction temperature or other inorganic base such as K₂CO₃, Cs₂CO₃, and K₂HPO₄ resulted in lower yields.

A broad range of alkenyl and aryl iodides, including both electron-rich and electron-deficient variants, were found to be reactive, with sterically demanding substrates and heteroaryl iodides also providing products in moderate to high yields. Additionally, the reaction proceeded well with various nitrogen nucleophiles, including phthalimides, Ts-protected amines, hydroxamic acids, and azaheterocycles, which are relevant to medicinal chemistry.

Reactions with internal, unactivated alkenes afforded carboaminated products (60d), albeit in moderate yield and with low diastereoselectivity. In contrast, a variety of α-substituted terminal alkenes were viable substrates, where the steric properties of the α-substituent significantly influenced diastereoselectivity—bulkier substituents led to higher stereoselectivities (60e, 60f).

The authors considered multiple reaction pathways, including one involving aminopalladation to form a five-membered palladacycle followed by oxidative addition and reductive elimination, another featuring reversible proto-depalladation leading to a hydroaminated intermediate capable of reengaging in C–H activation, and a third pathway involving aza-Wacker addition, β-H elimination, oxidative addition, Heck-type carbopalladation, and proto-depalladation to generate the final product. After a series of mechanistic investigations, including reaction progress kinetic analysis, competition experiments, and computational analysis, the authors proposed the reaction mechanism (Fig. 19). First, the palladium(II) catalyst coordinates to the aminoquinoline directing group tethered to the alkene, followed by aminopalladation with the nitrogen nucleophile to form a five-membered palladacycle. Oxidative addition of the organohalide then generates a palladium(IV) intermediate, which undergoes reductive elimination and ligand exchange to afford the desired carboaminated product while regenerating the active catalyst.

Fig. 19 Proposed reaction mechanism.

Ni-Catalysis

This Engle group reported a nickel-catalyzed, three-component, umpolung strategy for the regioselective 1,2-carboamination of unactivated alkenyl carbonyl compounds (Fig. 20).⁴⁵ Notably, this method exhibits regioselectivity opposite to their previous work,⁴⁴ employing an electrophilic nitrogen reagent (O-benzoylhydroxylamine) and aryl/alkyl zinc reagents as carbon nucleophiles. While electrophilic aminating reagents have long been utilized for C–N bond formation, their application in nickel catalysis remains relatively underexplored.^46–50

Fig. 20 Nickel-catalyzed umpolung 1,2-carboamination of alkenyl carbonyl compounds.

In this reaction, regioselectivity is dictated by an 8-aminoquinoline directing group, which stabilizes the formation of a five- or six-membered intermediate. This strategy also mitigates side reactions such as β-hydride elimination and two-component cross-coupling, enhancing the overall efficiency of the transformation.

Through optimization studies, the authors found that the desired carboamination product (54a) was obtained in high yield (84%) using an alkene tethered with 8-aminoquinoline, commercially available Me₂Zn, and O-benzoylhydroxylamine as the electrophile, in the presence of Ni(cod)₂ in a diluted THF solution. The reaction exhibited broad electrophile scope, accommodating various N–O bond-containing nitrogen sources, including heterocyclic motifs (54a, 54b) and acyclic amine-derived reagents (54c, 54d), delivering the corresponding carboamination products in good yields. Regarding the carbon nucleophile scope, the reaction tolerated a wide range of diorganozinc and organozinc halides (54e–h), though some substrates gave lower yields. Additionally, the methodology was highly diastereoselective with internal alkenes (54i–j), furnishing syn-selective carboamination products as confirmed by X-ray crystallography. The reaction also extended to γ,δ-unsaturated alkenyl carbonyl compounds, yielding γ-amino acid derivatives (54k–l).

Two possible reaction pathways have been proposed (Fig. 21). In Pathway A, the mechanism begins with oxidative addition of the N–O electrophile, followed by transmetalation with dimethylzinc, migratory insertion, and reductive elimination to afford the desired product. Alternatively, in Pathway B, transmetallation occurs first, followed by migratory insertion and oxidative addition of the nitrogen electrophile, with reductive elimination leading to the same product. Preliminary mechanistic studies, including radical clock and inhibitor experiments, suggest that oxidative addition proceeds via a two-electron pathway rather than a single-electron transfer (SET) mechanism.

Fig. 21 Plausible reaction pathways.

Although the strategy of using 8-aminoquinoline as a directing auxiliary enhanced both reactivity and stereoselectivity, the use of 8-aminoquinoline required additional steps for auxiliary installation and removal, reducing the overall efficiency of the process (Fig. 22A). Moreover, organozinc reagents, which were used as carbon nucleophiles, were highly sensitive to air and moisture, which increased operational complexity and limited their practicality under standard laboratory conditions.

Fig. 22 Nickel-catalyzed 1,2-carboamination of alkenyl alcohols.

To address this limitation, recent studies have introduced a nickel-catalyzed 1,2-carboamination strategy utilizing hydroxyl groups as directing functional groups (Fig. 22B).⁵¹

Initial attempts with substrates such as 4-phenylbutanol (55) and PhB(nep) (57) resulted in significant side-product formation, including the oxidative Heck product (b) and esterified starting alcohol (c), when O-benzoyl hydroxylmorpholine was employed as the electrophilic aminating reagent (Fig. 22C).

The authors successfully suppressed the formation of these side products through the use of sterically and electronically tuned N–O reagents. Electron-rich and sterically hindered benzoyl electrophiles improved product yield by minimizing side product formation, with the 2,6-dimethoxybenzoyl group chosen for further study due to its optimal combination of steric and electronic properties.

The reaction scope investigation revealed that a wide range of aryl and alkenyl boronic esters can participate in this transformation, affording the corresponding carbonamination products (Fig. 23A). Regarding the nitrogen electrophile scope, six-membered azaheterocycles—including piperidine, N-Boc-protected piperazine, and thiomorpholine-derived electrophiles—provided good yields. Additionally, various substituted cyclic amines delivered the desired products in high yields.

Fig. 23 The selected scope of the reaction and proposed mechanisms.

The reaction also exhibits broad alkene substrate compatibility, as allyl and bishomoallyl alcohols underwent successful transformations, demonstrating tolerance for varying chain lengths. Moreover, secondary and tertiary alcohols, as well as phenol, served as effective native directing groups, affording the desired products in good yields. Notably, reactions with disubstituted alkene substrates—typically more challenging due to steric hindrance in the migratory insertion step—showed that both 1,1- and 1,2-disubstituted alkenes were compatible under the reaction conditions, albeit with lower yields.

A gram-scale reaction experiment was also conducted, demonstrating good yields, further highlighting the efficiency and practicality of this method in synthetic applications.

The proposed mechanism (Fig. 23B) involves an initial transmetalation of Ni(I), followed by coordination with the alkene substrate. Subsequent alcohol-directed syn-selective migratory insertion forms a putative alcohol-coordinated alkyl nickelacycle. This intermediate then undergoes oxidative addition with the electrophilic aminating reagent, setting the stage for the final C–N reductive elimination step that furnishes the 1,2-carboaminated product.

Building on prior work involving the direct 1,2-carboamination of alkenes with hydroxyl groups, the Engle group has extended the research to free alkenyl amines (Fig. 24).⁵²

Fig. 24 Alkene difunctionalization directed by free amines.

The author optimized the N–O electrophile leaving group and selected tert-butyl, tert-amyl, and cyclohexylcarbonyl substituted N–O reagents as electrophile components. Specifically, they employed O-benzoyl hydroxylamine derivatives as the electrophilic nitrogen source. Through systematic evaluation, they found that electron-donating groups at the ortho-positions of the electrophile enhanced the yield of the desired product by suppressing undesired side reactions. The use of sterically bulkier and more electron-donating substituents on the benzoyl electrophiles further increased product yields.

The choice of t-AmOH as solvent was crucial to achieve high yields as other solvents such as THF, 1,4-dioxane, or i-BuOH failed to deliver the desired product.

In addition to exploring the scope of nucleophiles and electrophiles, the study also investigated a variety of secondary alkenyl amine substrates (Fig. 25). Remarkably, excellent yields were achieved with linear amine substrates, and high diastereomeric ratios (>20 : 1) were observed with acyclic and cyclic (Z)-alkenes.

Fig. 25 The selected substrate scope.

However, a significant erosion of diastereoselectivity was noted with (E)-alkene substrates. This observation suggests the potential involvement of a competitive process, wherein reversible homolysis of alkyl–Ni(III) intermediates generates an alkyl radical and Ni(II), influencing the stereochemical outcome.⁵³

The authors tested terminal diene substrates with two possible reactive sites and observed the exclusive formation of a single product, demonstrating superior chemoselectivity for the homoallylic alkene (Fig. 26A). This result highlights the preferential formation of a five-membered nickelacycle, which is favored over a four-membered alternative, as the key factor driving the observed selectivity. Notably, this method enables differentiation between two sterically and electronically similar terminal alkenes solely based on tether length, a distinction that is not achievable with weaker directing groups or radical insertion-based reactions.

Fig. 26 (a) Regioselective 1,2-carboamination of a dienyl amine. (b) Proposed mechanism.

As a proposed mechanism (Fig. 26B), the process begins with the transmetalation step, followed by alkene coordination.

Afterward, migratory insertion occurs, facilitating the insertion of the alkene into the Ni–C bond. This is followed by an oxidative addition/reductive elimination sequence, where the nickel center cycles between Ni(I) and Ni(III) oxidation states. This cycle ultimately leads to the formation of the desired product.⁵⁴

Despite the recent progress, the simultaneous installation of diverse carbon and nitrogen functionalities onto unactivated alkenes remains underexplored. In 2023, Engle group introduced a ligand design strategy that enables nickel-catalyzed three-component carboamidation (Fig. 27), providing a versatile approach for a broad range of alkenyl amine derivatives. This tandem process operates through alkyl migratory insertion followed by inner-sphere metal–nitrenoid transfer, offering an efficient and general platform for alkene functionalization.⁵⁵

Fig. 27 Ligand-enabled carboamidation of unactivated alkenes through enhanced organonickel electrophilicity.

The development of 1,4-benzoquinone ligands with alkyl substituents at the C2 and C5 positions demonstrated improved yields compared to the conventional DQ ligand.⁵⁶ Among these, the optimized ligands (Fig. 27B) exhibited high yields across a broad range of alkene substrates, including those with electron-rich sulfonamides and challenging alkene motifs. Especially, the study revealed the influence of its isopropyl group, which displays reduced electron-donating ability. This electron-withdrawing characteristic was found to favor the migratory insertion step by stabilizing the Ni–C bond during interaction with the alkene substrate, thus enhancing the efficiency of the catalytic cycle.

In the scope (Fig. 28) of sulfonamide substrates, the sulfonyl substituents exhibit consistent results regardless of the sulfonamide's electronic and steric properties. Consequently, 1,4-disulfonamides demonstrate excellent regioselectivity. Moreover, the bench-stable nature of new Ni catalyst allows for satisfactory yields without requiring a glovebox.⁵² The reaction of alkenylsulfonamide with an internal (E)-olefin was found to yield the desired carboamidation product with high diastereoselectivity, having two stereocentres in the sulfonamide moiety. Reactions with aminoquinoline (AQ)-directed functional groups were attempted by varying the number of methylene units. It was found that the yield was highest when the methylene linker consisted of three units.

Fig. 28 The selected substrate scope.

Radical approaches

Recent advances in photoredox and electrocatalysis have enabled the selective generation of radical species under mild conditions, facilitating numerous novel organic transformations. The addition of radical intermediates to alkenes provides a powerful approach for forming new C–C or C–N bonds, with the potential for subsequent bond formation. However, preserving the stereochemical integrity of the starting alkenes is inherently challenging, as radical addition generates an sp²-hybridized carbon-centered radical. Nonetheless, stereoselective bond formation in the subsequent step can yield amines with high stereocontrol. This can be achieved through substrate control, where regioselectivity is governed by the stability of the intermediate radical and steric/electronic factors that influence stereochemical outcomes in the final bond-forming step. Alternatively, stereoselectivity can be induced by capturing the radical intermediate with a Cu catalyst bearing a chiral ligand. In this section, we discuss recent advances that leverage these strategies to achieve stereoselective three-component alkene difunctionalization for amine synthesis.

Pd-Catalysis

1,3-Dienes are versatile and widely used starting material in organic synthesis, and their difunctionalization enables efficient access to complex molecules in a single step. Specifically, 1,2-carboamination provides a direct route to allylic amines, which are valuable in synthesis and bioactive compounds. However, reported examples remain limited, with most involving two-component annulative reactions at high temperatures.

To overcome these limitations, the Gevorgyan group reported a light-induced Pd-catalyzed three-component coupling of 1,3-dienes, alkyl iodides, and amines under mild conditions (Fig. 29).⁵⁷ This transformation proceeds via a hybrid π–allyl palladium radical intermediate, which undergoes a radical-polar crossover to form a traditional π–allyl palladium species, enabling nucleophilic trapping by amines.

Fig. 29 Photoinduced, intermolecular 1,2-carboamination of 1,3-dienes.

Through the optimization study using 1-phenylbutadiene (69), (trimethylsilyl)methyl iodide (71), and N-methylbenzylamine (70), the authors identified reaction conditions that effectively suppress various side reactions, including Heck, hydroamination, S_N2, and 1,4-addition pathways (Fig. 29A). Under blue LED irradiation, the desired 1,2-carboamination product (72a) was obtained in 89% yield using a PdCl₂ catalyst, Xantphos ligand, AgNTf₂ additive, and Cs₂CO₃ as a base. In the absence of blue LED or Pd catalyst, the formation of S_N2 side products was mainly observed. The yield was significantly lower without AgNTf₂ (48%) and a lower yield (44%) and selectivity were observed in the absence of Cs₂CO₃.

Following an extensive mechanistic investigation, the authors proposed that upon photoexcitation, LnPd⁰ (I) undergoes a single-electron transfer (SET) with the alkyl iodide, generating a hybrid alkyl–palladium radical species (II). This intermediate adds to the terminal position of the diene, forming radical species (III), which equilibrates with the π–allyl complex (IV). In the presence of a triflimide anion, this equilibrium shifts toward complex IV, as supported by mechanistic experiments using synthesized π–allyl palladium complexes with a Xantphos ligand and two different counterions (iodide and triflimide). The subsequent nucleophilic attack by the amine on complex IV yields the desired carbofunctionalization product while regenerating the active Pd catalyst (Fig. 29B). When the reaction was performed with other ligands, the yield ranged from 0 to 12%, but when the Xantphous ligand was used, the yield increased to 94% (GC yield).

The methodology was found to be general across various dienes, including aryl-, heteroaryl-, and alkyl-substituted dienes, with good chemoselectivity and tolerance for electron-rich and electron-deficient groups (Fig. 30). The reaction proceeded smoothly with a range of alkyl iodides, with primary and secondary iodides affording the desired products, though regioselectivity challenges arose with bulkier substrates. Secondary amines, including benzylamines, aliphatic acyclic amines, and heterocyclic amines (e.g., pyrrolidine, piperidine), participated efficiently, with heterocycles showing higher reactivity. Even less nucleophilic N-methylaniline and indoline reacted successfully, and allylic amines produced di- and triallylamines, though in lower yields. Notably, the methodology was applicable to complex molecules, as demonstrated by the successful modification of ciprofloxacin and desloratadine derivatives.

Fig. 30 The selected substrate scope.

Combining the Heck reaction with allylic substitution has emerged as a powerful strategy for the difunctionalization of 1,3-dienes using palladium catalysis via oxidative addition, migratory insertion, and allylic substitution. However, traditional interrupted Heck/allylic substitution cascades have been largely limited to activated or sp²-hybridized aryl and vinyl electrophiles, restricting their broader synthetic applicability.⁵⁸ To address this limitation, the Glorius group developed a radical-based approach that enables interrupted Heck/allylic substitution cascades with sp³-hybridized aliphatic electrophiles.⁵⁹

This strategy (Fig. 31A) relies on the formation of hybrid alkyl Pd(I) radical intermediates (I) from unactivated tertiary alkyl bromides under photoinduced palladium catalysis, which subsequently undergo radical addition to 1,3-dienes, generating hybrid allylic Pd(I) radical species (II). Following radical recombination, π–allylpalladium complexes (III) are formed, which can then be intercepted by various nucleophiles to deliver the desired products while regenerating the palladium catalyst.

Fig. 31 Radical three-component coupling with unactivated alkyl bromides and 1,3-dienes.

After evaluating various reaction parameters, the authors identified optimal conditions using Pd(PPh₃)₄ (10 mol%), BINAP (12 mol%), and KOAc (150 mol%) in DMA at room temperature under blue LED irradiation, yielding the three-component coupling product 76 with 60% yield and excellent selectivity (>95 : 5 dr, >20 : 1 rr, Fig. 31B).

Condition-based sensitivity screening showed that the reaction is sensitive toward low light intensity, lower reaction temperature, and high oxygen concentration. Also, the reaction can be scaled up by a factor of 20 without a significant drop in reaction yield. The substrate scope investigation revealed that this radical platform accommodates a broad range of nitrogen-, oxygen-, sulfur-, and carbon-based nucleophiles. Notably, nitrogen-based nucleophiles provided excellent yields, and the reaction was successfully extended to unactivated primary and secondary amines (Fig. 32). Additionally, the methodology demonstrated remarkable generality, tolerating a diverse array of 1,3-dienes and alkyl halides. Across more than 130 examples, the reaction efficiently formed sequential C(sp³)–C(sp³) and C–X bonds with exceptional regio- and diastereoselectivity (mostly >95 : 5 dr, >20 : 1 rr).

Fig. 32 Three-component, interrupted radical Heck/allylic substitution cascade involving unactivated alkyl bromides.

Recently, the Ritter group described visible-light-induced, three-component palladium-catalyzed 1,4-aminoarylation of butadienes with readily available aryl halides and aliphatic amines addressing critical challenges in achieving regioselective and stereoselective transformations (Fig. 33A).⁶⁰ This reaction not only achieves exceptional chemo- and regioselectivity but also delivers E-configured allylamines in a single-step process. The strategy centers on the use of Pd(PPh₃)₄ and rac-BINAP as catalysts under blue LED irradiation (Fig. 33B).

Fig. 33 1,4-Aminoarylation of butadienes via photoinduced palladium catalysis.

After in-depth mechanistic investigation, including UV/Vis spectroscopy, high-resolution mass spectrometry (HRMS), and TEMPO trapping experiments, the author proposed that upon the irradiation of visible light, aryl radicals are generated through SET or XAT, which is influenced by the reduction potential and mesolytic cleavage rates of the aryl halides. These radicals add to the butadiene substrate, generating an allyl Pd(II) intermediate, which then undergoes Tsuji–Trost allylation to produce the final product. A small Hammett ρ value of 0.5 further supports the radical nature of the transition state, emphasizing the novel mechanistic aspects of this study.

The substrate scope of this reaction is notably broad (Fig. 34). It works well with various aryl halides, including electron-rich, neutral, and deficient substrates. While aryl bromides and chlorides show high reactivity, aryl iodides exhibit lower conversions due to rapid oxidative addition. Secondary aliphatic amines show excellent reactivity and selectivity, whereas primary amines and weakly nucleophilic amines demonstrate reduced activity and increased byproduct formation. The reaction also accommodates different butadiene derivatives, though substituents can influence reaction rates and stereochemical outcomes. For instance, methyl-substituted butadienes exhibit slower reaction rates and increased formation of stereoisomeric mixtures. Primary aliphatic amines (80g), which have relatively weaker nucleophilicity, exhibit low reactivity and lead to the formation of Heck coupling byproducts due to their slower reaction rate with allylPd(II) species. Amines with weak nucleophilicity (80h–j), including N-heteroaromatics, anilines, sulfonamides, imides, and carbamates, did not yield the desired products in the reaction.

Fig. 34 Selected substrate scope.

Cu-Catalysis

In 2012, Fu and Peters reported photoexcited Cu(I)-hetero nucleophile complexes that produce alkyl radicals through SET reduction of alkyl halides.⁶¹ Recombination of these radicals with nucleophilic ligands led to new C–C or hetero bond formation. Inspired by those elegant works, significant progress has been made in the development of radical-type reactions in three-component alkene difunctionalization with a new C–N bond for the synthesis of amines.

For example, in 2019, Zhang reported carboamination of alkenes using amines as a nitrogen source and alkyl halides as a carbon source of the reaction (Fig. 35).⁶² Specifically, in this reaction, fluoroalkyl halides are used as a carbon source, so this reaction can be used to synthesize fluorinated nitrogen-containing organic compounds.

Fig. 35 Scopes of Cu-catalyzed carboamination of alkenes using various amines and alkyl halides. ^a According to reaction condition A. ^b According to reaction condition B.

The methodology demonstrated high efficiency, yielding good yields across a diverse range of amines and alkyl halides. Both fluorinated and non-fluorinated alkyl halides readily participated in the carboamination of alkenes, serving as effective carbon sources of reaction. Notably, for simple amines with a reduced π-system, the inclusion of rac-BINOL was essential. This observation suggests that the π-system plays a crucial role in photoexcitation and single-electron transfer (SET) within the Cu–Nu complex, with the Cu–BINOL complex undergoing photoexcitation and SET in place of the Cu–N complex.

As a proposed mechanism (Fig. 36), ligand exchange of copper catalyst with nucleophiles in the presence of base generates Cu(I)–Nu complex (II) first. When amines with the reduced π-system, BINOL participates in ligand exchange step. Upon the irradiation of blue LED light, the excited-state Cu(I)–Nu complex (III) undergoes Single electron transfer with alkyl halides to generate Cu(II)–Nu complex (V) and alkyl radicals. The alkyl radicals then add to alkenes and a new carbon-centered internal radicals. Lastly, bond formation between the nucleophile and the radical could occur through two possible pathways. In path (a), capturing of the carbon-centered radical by LnCu(II)NR²R³ (V) could generate the Cu(III) complex (VI), which undergoes reductive elimination to afford the desired products and regenerate the active Cu(I) catalyst (I). Alternatively, a single electron transfer process (path b) could also give the same products.

Fig. 36 Proposed catalytic cycle.

1,2-Aminooxygenation of 1,3-dienes is a powerful synthetic method that enables the installation of both amino and alcohol groups and therefore synthesizes substituted allylic systems in a single step.⁶³ N-Substituted pyridinium salts are one of the key reagents that enable this transformation by the generation of diverse radicals through SET reduction.^64,65

In 2022, the Chen group reported selective three-component 1,2-aminooxygenation of 1,3-dienes with easily available N-aminopyridinium salts as N-centered radical precursors and commercially available alcohols as oxygen nucleophiles under dual photoredox and copper catalysis (Fig. 37).⁶³ The protocol provides a modular and practical approach for the construction of diversely substituted 1,2-aminoalkoxylation products with good yields and regioselectivity.

Fig. 37 The selected scope of Cu-catalyzed aminoalkoxylation of 1-aryl-1,3-dienes using various N-aminopyridinium salts and alcohols. ^a Using CH₂Cl₂ as solvent, ^b using CH₂Cl₂/MeCN as solvent.

Achieving high regioselectivity in 1,3-diene functionalization, (1,2- vs. 1,4-addition), is inherently challenging. However, the authors successfully developed a reaction system that delivers the 1,2-aminoalkoxylation product exclusively. This was accomplished using a dual catalytic system comprising the organic photocatalyst 10-phenylphenothiazine (Ph-PTZ, 5.0 mol%) and Cu(CH₃CN)₄PF₆ (20 mol%).

The methodology exhibited a broad substrate scope, demonstrating good yields across a wide range of N-aminopyridinium salts and alcohols. Additionally, 1,3-disubstituted 1,3-dienes effectively participated in the reaction, affording aminooxygenated products with tetrasubstituted carbon centers in good yields.

The proposed mechanism (Fig. 38) involves the excitation of Ph–PTZ under purple light, leading to a single-electron transfer (SET) with N-aminopyridinium salt to generate an amidyl radical. This nitrogen-centered radical undergoes regioselective addition to a 1,3-diene, forming a stabilized carbon radical, which is then oxidized to a carbocation by Ph–PTZ˙⁺ or Cu(II). Subsequent nucleophilic attack of methanol yields the final product, with Cu(CH₃CN)₄PF₆ playing a crucial role in enhancing regioselectivity. Although Cu(CH₃CN)₄PF₆ alone exhibited some photoredox activity, attempts to develop an asymmetric variant using a chiral ligands were unsuccessful due to weak methanol coordination with copper.

Fig. 38 Proposed mechanism of Cu-catalyzed selective 1,2-aminoalkoxylation of 1-aryl-1,3-dienes.

The transformation of CO₂ into valuable chemicals is a key goal for sustainable development. Among various approaches, the difunctionalizing carboxylation of alkenes with CO₂ stands out as an efficient method for constructing complex carboxylic acids and their derivatives. However, existing strategies have been largely restricted to monocatalytic systems and specific reaction types.⁶⁶

Recently, Ye and Yu group reported a synergistic approach for the aminocarboxylation of alkenes with CO₂, offering an efficient and practical synthetic route to valuable β-amino acids (Fig. 39).⁶⁷

Fig. 39 The reaction scope and synthetic application for aminocarboxylation of alkenes with CO₂.

CO₂ and amine can react directly to make carbamate salts, which can be used in valuable reactions in organic synthesis.⁶⁸ Besides, it is difficult to control the single-electron activation of alkenes, which can cause side reaction such as dimerization and hydrogen-atom transfer, if the radicals are not trapped by appropriate electrophiles.^69,70 In order to succeed the aim of the amino carboxylation of alkenes with CO₂, the catalysts were the binaphthol derivatives for photocatalysis and the copper catalyst for cooperative transition metal catalysis.

The reaction exhibits a broad scope. In addition to styrene-type alkenes, various acrylates can also be utilized, yielding the corresponding products with excellent regioselectivity. Furthermore, derivatives of complex biological molecules are compatible with this system. Lastly, the reaction was successfully scaled up to a 5 mmol scale, demonstrating its practicality. Notably, it can be further transformed into a β-lactam-containing product, a common motif in pharmaceuticals.

As proposed in the mechanism (Fig. 40), binaphthol (ArOH) is initially deprotonated by KOtBu to form ArO⁻. Under blue LED irradiation, the excited ArO* oxidizes vinylarenes, generating radical species (ArO˙) and radical anion intermediates. These intermediates undergo a highly regioselective reaction with CO₂, leading to the formation of benzylic radicals. ArO˙ can be reduced back to ArO⁻ by CuI, which is then oxidized to Cu^II. The Cu^II complex undergoes ligand exchange with an amine to form Cu^II(NR₁R₂), facilitating C–N bond formation with the benzylic radical. This step yields the desired product while regenerating the Cu^I catalyst, completing the catalytic cycle. This strategy uniquely integrates photocatalysis with copper catalysis, achieving rare orthogonal difunctionalization of alkene radical anions under redox-neutral conditions.

Fig. 40 The proposed mechanism for aminocarboxylation of alkenes with CO₂.

Fluorinated compounds are widely utilized in pharmaceuticals, agrochemicals, and materials due to their unique physical and biological properties. For example, α,α-difluoromethylamines serve as amide bioisosteres, offering potential applications in drug discovery. However, defluorination of trifluoromethyl (–CF₃) groups remains highly challenging due to the strong C–F bond dissociation energy (BDE). Activating these inert C–F bonds to form C–N linkages presents a significant synthetic hurdle.

In 2023, a photoexcited copper catalysis that activates C–F bonds in trifluoromethylated arenes, enabling reactions with carbazoles and aromatic amines are reported (Fig. 41A).⁷¹

Fig. 41 Photoinduced copper-catalyzed C–N coupling with trifluoromethylated arenes.

This method provides a variety of α,α-difluoromethylamine and imidoyl fluoride syntheses, both of which are valuable due to their biological and chemical importance. The copper-based photocatalyst operates by an inner sphere electron transfer mechanism to generate difluoromethyl radicals as key intermediates, which interact with nitrogen sources in the presence of specific ligands to undergo selective C–N coupling.

In light of recent successes with PNP ligands,⁷² the reaction was carried out using a carbazole-centered PNP ligand (L1) to achieve copper-catalyzed C–N coupling of trifluoromethylated arenes and anilines. The resulting α,α-difluoromethylamine was converted to imidoyl fluoride via tandem C–N coupling and defluorination under basic conditions. Building on the unique reactivity of α,α-difluorobenzylic radical intermediates in defluorinative C–N coupling, the authors explored whether alkenes could be incorporated into the reaction system to achieve 1,2-difluoroalkylamination. This approach provides a novel route for synthesizing γ,γ-difluoroalkylamines, bioisosteres of β-aminoketones. Screening various alkenes revealed that styrenes were the most effective radical acceptors, whereas aliphatic alkenes primarily yielded imidoyl fluorides with only trace amounts of the desired 1,2-difunctionalized products, likely due to the instability of the corresponding alkyl radicals and their inefficient interaction with copper species. The reaction demonstrated broad functional group tolerance, accommodating silanes, halides, and methoxy groups with moderate yields. ortho-Substituted styrenes had minimal impact on efficiency, while 1,1-disubstituted olefins, internal alkenes, and electron-deficient alkenes were also viable substrates.

As a proposed mechanism (Fig. 42), upon visible light irradiation, the Cu catalyst [L1Cu^I] (I) is excited and undergoes either an outer-sphere (OSET) or inner-sphere (ISET) single electron transfer, leading to the formation of key radical intermediates (V) and [L1Cu^II–F] complex (III). After the radical addition to alkene, the resulting benzylic radical is captured by [L1Cu^II–NHAr] complex (IV) generated by ligand exchange with arylamines, and undergoes C–N bond formation to give the desired product.

Fig. 42 The proposed mechanism.

Enantioselective reactions

Enantioenriched 2,2-diarylethylamine is crucial for the development of dopamine receptor agonists and thus has broad potential in bioactive molecule design.⁷³ One efficient method for synthesizing this optically active structure is the enantioselective aminoarylation of alkenes using transition metal catalysts. However, most reported reactions have been intramolecular in nature, as intermolecular reactions are challenging due to the high entropic cost associated with unfavorable interactions between the alkene and amine. The addition of highly reactive amino radical species to styrenes typically proceeds with a low energy barrier, leading to the formation of benzylic radicals. Subsequent functionalization of these intermediates enables access to diverse amination products. However, due to the inherent reactivity of radical species, achieving enantioselective control in these transformations remains a significant challenge.⁷⁴

In 2017, Lin and Liu groups reported an innovative solution by utilizing a facile reaction between amino radical and styrenes to generate benzylic radicals (Fig. 43).⁷⁵

Fig. 43 Asymmetric copper-catalyzed intermolecular aminoarylation of styrenes.

In 2013, the Fu group demonstrated that a benzylic radical could undergo highly enantioselective reactions with L*Ni–Ar complexes.⁷⁶ Additionally, benzylic radicals can also react enantioselectively with Cu–Ar complexes. Building on this, the enantioselective arylation of benzyl radicals with copper catalysts led to the hypothesis that β-aminobenzylic radicals could be coupled enantioselectively with LCu(II)–Ar species, allowing for precise control of the reaction.⁷⁷

Initial studies on the reaction with NFSI and PhB(OH)₂ using an achiral (phen)Cu(I) catalyst yielded the desired product in low yield (19%), but the use of chiral ligand L1 increased the yield to 35% with an enantiomeric excess (ee) of 84%. DFT calculations showed that reducing the electrophilicity of the amino radical could slow the radical addition step to match the slower transmetalation process. After evaluation of various N–F reagents, optimization using NFASH, along with the addition of LiOtBu, increased the yield to 77% without affecting enantioselectivity, and extending the reaction time further improved the yield to 81%.

The substrate scope was evaluated for both α-vinylnaphthalenes and vinylbenzenes, with electron-rich and electron-poor variants providing products in good yields and high enantioselectivities. β-Vinylnaphthalenes also showed good reactivity, giving products with high yields and ee. Various styrenes, including para-, meta-, and ortho-substituted, as well as di- and tri-substituted styrenes, gave corresponding products with good yields and enantioselectivities. The scope of arylboronic acids was also explored, with both electron-rich and electron-poor p-arylboronic acids giving products with excellent enantioselectivities, while thiophenyl- and benzothiophenylboronic acids also delivered the target products with excellent ee.

To demonstrate the synthetic utility of the reaction, further synthesis of bioactive compounds was carried out. This method enabled the synthesis of a range of biologically active compounds, showcasing its broad applicability. These examples highlight the potential of enantioselective intermolecular aminoarylation as a valuable tool in the synthesis of chiral bioactive molecules.

The proposed mechanism (Fig. 44B) begins with the reaction of alkylsulfonamide (NFAS) with L*Cu(I), generating an amino radical. This amino radical then reacts with styrene to form a β-aminobenzylic radical and an L*Cu(II) complex. The L*Cu(II) complex subsequently reacts with arylboronic acids to form the L*Cu(II)–Ar species. The β-aminobenzylic radical undergoes enantioselective coupling with the L*Cu(II)–Ar complex through asymmetric aminoarylation, resulting in the formation of enantiopure 2,2-diarylethylamines.

Fig. 44 The product derivatization and reaction mechanism for Cu-catalyzed aminoarylation.

The chiral β-amino nitrile is found in a wide range of natural products, and its efficient synthesis can be useful in drug design, agrochemistry, and chiral ligand synthesis in asymmetric catalysis.^78,79 The chiral β-amino nitrile can be synthesized with the Mannich reaction involving an alkyl nitrile in an imine,⁷⁹ but this might be expensive and require pre-functionalisation steps to make the product optically active. The more economical method to make β-amino nitrile would be to synthesize it by the difunctionalization of alkenes by transition metal catalysis. However, metal catalysis could be to side reactions like β-hydride elimination that limit the scope of the low regiocontrol when without a directing group.

The Nicewicz group has developed numerous regioselective anti-Markovnikov hydrofunctionalization and difunctionalization methods for alkenes.^80,81 Their common mechanism starts with the acridinium salt and blue LEDs, resulting in the oxidation of the olefin to the cationic radical. Then, the nucleophile, such as amine, is added to this electrophilic intermediate with excellent anti-Markovnikov regioselectivity, and the radical intermediate is captured with a co-catalyst to proceed with the reaction. Previous works had used the hydrogen atom transfer catalyst for hydrofunctionalization, but after the work of the Stahl and Liu group that made the first methods for enantioselective cyanation of benzylic C–H bonds with chiral copper catalyst,⁸² they hypothesized that it could be produced by using a chiral copper co-catalyst.⁸³

The reaction optimization (Fig. 45) began by combining previously reported hydroamination conditions with benzylic cyanation methods, using 4-tert-butylstyrene as the model substrate. Cu(II) triflate and tert-butyl hydrogen peroxide (TBHP) were found to give the high yields and enantioselectivity, yielding 35% of the desired product and 80% enantiomeric excess (ee). Ligand screening revealed that the sBOX(i-Pr) ligand was the most effective. Evaluation of solvents showed that MeCN gave the best enantioselectivity while using ethyl acetate (EtOAc) can improve the yield. Not surprisingly, higher temperature resulted in lower enantioselectivity.

Fig. 45 The reaction scope for enantioselective aminocyanation.

The reaction was extended to a variety of nucleophiles, such as simple carbamates and azoles, producing β-amino nitriles with good to excellent yields (43–69%) and ee (79–90%). Styrene derivatives, both terminal and internal, also gave moderate to good yields and excellent enantioselectivities (81–99% ee). The reaction was successfully applied to drug derivatization, demonstrating the potential of this catalytic transformation for bioactive compound synthesis.

As a proposed mechanism (Fig. 46), the Mes–Acr–BF₄ photocatalyst was excited by 456 nm LEDs to Mes–Acr–BF₄*. Substrate alkene is oxidated by the excited photocatalyst, then makes a new bond with amine by nucleophilic addition. In a similar mechanism proposed by the Stahl and Liu group,⁸² the alkyl radical adds to the copper complex (L*Cu(II)–CN). The product would be released by reductive elimination. The tert-Butyl hydroperoxide (TBHP) can both oxidize the Mes–Acr–BF₄ radical and Cu(I) complex to regenerate the catalyst.

Fig. 46 The reaction mechanism for enantioselective aminocyanation.

Conclusion and outlook

Three-component, stereoselective alkene difunctionalization has become a powerful strategy for amine synthesis, overcoming key challenges in regio- and stereoselectivity. Advances in transition-metal catalysis, radical-mediated pathways, and directing-group-free methodologies have expanded the accessibility of C(sp³)–N bond formation, enabling the efficient construction of structurally complex and biologically relevant molecules. These innovations have significantly improved synthetic efficiency and streamlined the preparation of stereochemically defined amines.

Despite these advances, several challenges must be addressed to broaden the applicability of these methods. Expanding stereoselective alkene difunctionalization to accommodate diverse alkene substrates without directing groups remains a major goal. Additionally, developing highly enantioselective and scalable transformations under mild conditions is crucial for further practical utility. Addressing limitations such as reaction reproducibility, scalability, and catalyst cost will be essential for real-world applications. Moving forward, advances in catalyst design, reaction discovery, and mechanistic studies will play a critical role in refining existing methodologies and unlocking new opportunities in medicinal chemistry, materials science, and beyond.

Data availability

No primary research results, software, or code have been included, and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This paper was supported by Konkuk University in 2024.

References

1. N. A. McGrath, M. Brichacek and J. T. Njardarson, A Graphical Journey of Innovative Organic Architectures That Have Improved Our Lives, J. Chem. Educ., 2010, 87, 1348–1349.
2. E. Vitaku, D. T. Smith and J. T. Njardarson, Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals, J. Med. Chem., 2014, 57, 10257–10274.
3. J. F. Hartwig, Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism, Angew. Chem., Int. Ed., 1998, 37, 2046–2067.
4. T. Henkel, R. M. Brunne, H. Müller and F. Reichel, Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds, Angew. Chem., Int. Ed., 1999, 38, 643–647.
5. R. M. Romero, T. H. Wöste and K. Muñiz, Vicinal Difunctionalization of Alkenes with Iodine(III) Reagents and Catalysts, Chem. – Asian J., 2014, 9, 972–983.
6. R. I. McDonald, G. Liu and S. S. Stahl, Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications, Chem. Rev., 2011, 111, 2981–3019.
7. K. H. Jensen and M. S. Sigman, Mechanistic approaches to palladium-catalyzed alkene difunctionalization reactions, Org. Biomol. Chem., 2008, 6, 4083–4088.
8. R. Li, H. Zhang, B. Yu and H. Huang, Chemo- and regioselective cyclization of diene-tethered enynes via palladium-catalyzed aminomethylamination, Org. Chem. Front., 2023, 10, 2988–2993.
9. K. Yang, J. Liu, D. Fu, L. Niu, S.-J. Li and Y. Lan, A theoretical study of selective radical relay and coupling reactions for alkene difunctionalization, Org. Chem. Front., 2023, 10, 4336–4341.
10. P. Roychowdhury, S. Samanta, H. Tan and D. C. Powers, N-Amino pyridinium salts in organic synthesis, Org. Chem. Front., 2023, 10, 2563–2580.
11. J. Sun, L. Wang, G. Zheng and Q. Zhang, Recent advances in three-component radical acylative difunctionalization of unsaturated carbon–carbon bonds, Org. Chem. Front., 2023, 10, 4488–4515.
12. V. C. M. Gasser, S. Makai and B. Morandi, The advent of electrophilic hydroxylamine-derived reagents for the direct preparation of unprotected amines, Chem. Commun., 2022, 58, 9991–10003.
13. Z. Wu, M. Hu, J. Li, W. Wu and H. Jiang, Recent advances in aminative difunctionalization of alkenes, Org. Biomol. Chem., 2021, 19, 3036–3054.
14. X. Chen, F. Xiao and W.-M. He, Recent developments in the difunctionalization of alkenes with C–N bond formation, Org. Chem. Front., 2021, 8, 5206–5228.
15. T. Piou and T. Rovis, Rhodium-catalysed syn-carboamination of alkenes via a transient directing group, Nature, 2015, 527, 86–90.
16. S. Lee and T. Rovis, Rh(III)-Catalyzed Three-Component Syn-Carboamination of Alkenes Using Arylboronic Acids and Dioxazolones, ACS Catal., 2021, 11, 8585–8590.
17. C. W. Lamartina, C. A. Chartier, S. Lee, N. H. Shah and T. Rovis, Modular Synthesis of Unnatural Peptides via Rh(III)-Catalyzed Diastereoselective Three-Component Carboamidation Reaction, J. Am. Chem. Soc., 2023, 145, 1129–1135.
18. G. Li Petri, S. Di Martino and M. De Rosa, Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors, J. Med. Chem., 2022, 65, 7438–7475.
19. J. M. Palomo, Solid-phase peptide synthesis: an overview focused on the preparation of biologically relevant peptides, RSC Adv., 2014, 4, 32658–32672.
20. Y. Liu, D. S. Kim and M. C. Jewett, Repurposing ribosomes for synthetic biology, Curr. Opin. Chem. Biol., 2017, 40, 87–94.
21. W. Gong, G. Zhang, T. Liu, R. Giri and J.-Q. Yu, Site-Selective C(sp3)–H Functionalization of Di-, Tri-, and Tetrapeptides at the N-Terminus, J. Am. Chem. Soc., 2014, 136, 16940–16946.
22. H. M. Key and S. J. Miller, Site- and Stereoselective Chemical Editing of Thiostrepton by Rh-Catalyzed Conjugate Arylation: New Analogues and Collateral Enantioselective Synthesis of Amino Acids, J. Am. Chem. Soc., 2017, 139, 15460–15466.
23. W. Wang, J. Wu, R. Kuniyil, A. Kopp, R. N. Lima and L. Ackermann, Peptide Late-Stage Diversifications by Rhodium-Catalyzed Tryptophan C7 Amidation, Chem, 2020, 6, 3428–3439.
24. J. Zhang, J. Cao, L. Xu, Y. Zhou, T. Liu, J. Li and Y. Hu, Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors, Bioorg. Med. Chem., 2014, 22, 2955–2965.
25. T. Piou, F. Romanov-Michailidis, M. Romanova-Michaelides, K. E. Jackson, N. Semakul, T. D. Taggart, B. S. Newell, C. D. Rithner, R. S. Paton and T. Rovis, Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C–H Activation Reactions: An Experimental and Computational Study, J. Am. Chem. Soc., 2017, 139, 1296–1310.
26. T. Piou and T. Rovis, Electronic and Steric Tuning of a Prototypical Piano Stool Complex: Rh(III) Catalysis for C–H Functionalization, Acc. Chem. Res., 2018, 51, 170–180.
27. C. W. Lamartina, C. A. Chartier, J. M. Hirano, N. H. Shah and T. Rovis, Crafting Unnatural Peptide Macrocycles via Rh(III)-Catalyzed Carboamidation, J. Am. Chem. Soc., 2024, 146, 20868–20877.
28. F. Burg and T. Rovis, Diastereoselective Three-Component 3,4-Amino Oxygenation of 1,3-Dienes Catalyzed by a Cationic Heptamethylindenyl Rhodium(III) Complex, J. Am. Chem. Soc., 2021, 143, 17964–17969.
29. F. Burg and T. Rovis, Rh(III)-Catalyzed Intra- and Intermolecular 3,4-Difunctionalization of 1,3-Dienes via Rh(III)-π-Allyl Amidation with 1,4,2-Dioxazolones, ACS Catal., 2022, 12, 9690–9697.
30. N. Wagner-Carlberg and T. Rovis, Rhodium(III)-Catalyzed Anti-Markovnikov Hydroamidation of Unactivated Alkenes Using Dioxazolones as Amidating Reagents, J. Am. Chem. Soc., 2022, 144, 22426–22432.
31. N. Wagner-Carlberg and T. Rovis, Rhodium(III)-Catalyzed Remote Hydroamidation of Internal Alkenes Via Chain Walking, ACS Catal., 2023, 13, 16337–16343.
32. J. A. Gurak, K. S. Yang, Z. Liu and K. M. Engle, Directed, Regiocontrolled Hydroamination of Unactivated Alkenes via Protodepalladation, J. Am. Chem. Soc., 2016, 138, 5805–5808.
33. A. B. Weinstein and S. S. Stahl, Reconciling the Stereochemical Course of Nucleopalladation with the Development of Enantioselective Wacker-Type Cyclizations, Angew. Chem., 2012, 124, 11673–11677.
34. R. M. Fornwald, J. A. Fritz and J. P. Wolfe, Influence of Catalyst Structure and Reaction Conditions on anti- versus syn-Aminopalladation Pathways in Pd-Catalyzed Alkene Carboamination Reactions of N-Allylsulfamides, Chem. – Eur. J., 2014, 20, 8782–8790.
35. K. H. Jensen, T. P. Pathak, Y. Zhang and M. S. Sigman, Palladium-Catalyzed Enantioselective Addition of Two Distinct Nucleophiles across Alkenes Capable of Quinone Methide Formation, J. Am. Chem. Soc., 2009, 131, 17074–17075.
36. C. Martínez and K. Muñiz, Palladium-Catalyzed Vicinal Difunctionalization of Internal Alkenes: Diastereoselective Synthesis of Diamines, Angew. Chem., Int. Ed., 2012, 51, 7031–7034.
37. R. I. McDonald, G. Liu and S. S. Stahl, Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications, Chem. Rev., 2011, 111, 2981–3019.
38. D. R. White, J. T. Hutt and J. P. Wolfe, Asymmetric Pd-Catalyzed Alkene Carboamination Reactions for the Synthesis of 2-Aminoindane Derivatives, J. Am. Chem. Soc., 2015, 137, 11246–11249.
39. A. Joosten, A. K. Å. Persson, R. Millet, M. T. Johnson and J.-E. Bäckvall, Palladium(II)-Catalyzed Oxidative Cyclization of Allylic Tosylcarbamates: Scope, Derivatization, and Mechanistic Aspects, Chem. – Eur. J., 2012, 18, 15151–15157.
40. J. A. Keith and P. M. Henry, The Mechanism of the Wacker Reaction: A Tale of Two Hydroxypalladations, Angew. Chem., Int. Ed., 2009, 48, 9038–9049.
41. J. J. Dong, W. R. Browne and B. L. Feringa, Palladium-Catalyzed anti-Markovnikov Oxidation of Terminal Alkenes, Angew. Chem., Int. Ed., 2015, 54, 734–744.
42. M. J. MacDonald, D. J. Schipper, P. J. Ng, J. Moran and A. M. Beauchemin, A Catalytic Tethering Strategy: Simple Aldehydes Catalyze Intermolecular Alkene Hydroaminations, J. Am. Chem. Soc., 2011, 133, 20100–20103.
43. S.-B. Zhao, E. Bilodeau, V. Lemieux and A. M. Beauchemin, Hydrogen Bonding Directed Intermolecular Cope-Type Hydroamination of Alkenes, Org. Lett., 2012, 14, 5082–5085.
44. Z. Liu, Y. Wang, Z. Wang, T. Zeng, P. Liu and K. M. Engle, Catalytic Intermolecular Carboamination of Unactivated Alkenes via Directed Aminopalladation, J. Am. Chem. Soc., 2017, 139, 11261–11270.
45. V. A. van der Puyl, J. Derosa and K. M. Engle, Directed, Nickel-Catalyzed Umpolung 1,2-Carboamination of Alkenyl Carbonyl Compounds, ACS Catal., 2019, 9, 224–229.
46. Y.-R. Gu, X.-H. Duan, L. Yang and L.-N. Guo, Direct C–H Cyanoalkylation of Heteroaromatic N-Oxides and Quinones via C–C Bond Cleavage of Cyclobutanone Oximes, Org. Lett., 2017, 19, 5908–5911.
47. Y.-H. Chen, S. Graßl and P. Knochel, Cobalt-Catalyzed Electrophilic Amination of Aryl- and Heteroarylzinc Pivalates with N-Hydroxylamine Benzoates, Angew. Chem., Int. Ed., 2018, 57, 1108–1111.
48. H.-B. Yang, S. R. Pathipati and N. Selander, Nickel-Catalyzed 1,2-Aminoarylation of Oxime Ester-Tethered Alkenes with Boronic Acids, ACS Catal., 2017, 7, 8441–8445.
49. J. Xiao, Y. He, F. Ye and S. Zhu, Remote sp3 C–H Amination of Alkenes with Nitroarenes, Chem, 2018, 4, 1645–1657.
50. L. Wang and C. Wang, Ni-Catalyzed 1,2-iminoacylation of alkenes via a reductive strategy, Org. Chem. Front., 2018, 5, 3476–3482.
51. T. Kang, N. Kim, P. T. Cheng, H. Zhang, K. Foo and K. M. Engle, Nickel-Catalyzed 1,2-Carboamination of Alkenyl Alcohols, J. Am. Chem. Soc., 2021, 143, 13962–13970.
52. T. Kang, J. M. González, Z.-Q. Li, K. Foo, P. T. W. Cheng and K. M. Engle, Alkene Difunctionalization Directed by Free Amines: Diamine Synthesis via Nickel-Catalyzed 1,2-Carboamination, ACS Catal., 2022, 12, 3890–3896.
53. O. Gutierrez, J. C. Tellis, D. N. Primer, G. A. Molander and M. C. Kozlowski, Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings, J. Am. Chem. Soc., 2015, 137, 4896–4899.
54. H. Jiang and A. Studer, Intermolecular radical carboamination of alkenes, Chem. Soc. Rev., 2020, 49, 1790–1811.
55. Y. Hwang, S. R. Wisniewski and K. M. Engle, Ligand-Enabled Carboamidation of Unactivated Alkenes through Enhanced Organonickel Electrophilicity, J. Am. Chem. Soc., 2023, 145, 25293–25303.
56. L. Nattmann and J. Cornella, Ni(4-tBustb)3: A Robust 16-Electron Ni(0) Olefin Complex for Catalysis, Organometallics, 2020, 39, 3295–3300.
57. K. P. S. Cheung, D. Kurandina, T. Yata and V. Gevorgyan, Photoinduced Palladium-Catalyzed Carbofunctionalization of Conjugated Dienes Proceeding via Radical-Polar Crossover Scenario: 1,2-Aminoalkylation and Beyond, J. Am. Chem. Soc., 2020, 142, 9932–9937.
58. X. Wu and L.-Z. Gong, Palladium(0)-Catalyzed Difunctionalization of 1,3-Dienes: From Racemic to Enantioselective, Synthesis, 2019, 51, 122–134.
59. H.-M. Huang, P. Bellotti, P. M. Pflüger, J. L. Schwarz, B. Heidrich and F. Glorius, Three-Component, Interrupted Radical Heck/Allylic Substitution Cascade Involving Unactivated Alkyl Bromides, J. Am. Chem. Soc., 2020, 142, 10173–10183.
60. Y. Cai, G. Gaurav and T. Ritter, 1,4-Aminoarylation of Butadienes via Photoinduced Palladium Catalysis, Angew. Chem., Int. Ed., 2024, 63, e202311250.
61. S. E. Creutz, K. J. Lotito, G. C. Fu and J. C. Peters, Photoinduced Ullmann C–N Coupling: Demonstrating the Viability of a Radical Pathway, Science, 2012, 338, 647–651.
62. Y. Xiong, X. Ma and G. Zhang, Copper-Catalyzed Intermolecular Carboamination of Alkenes Induced by Visible Light, Org. Lett., 2019, 21, 1699–1703.
63. Y.-L. Wu, M. Jiang, L. Rao, Y. Cheng, W.-J. Xiao and J.-R. Chen, Selective Three-Component 1,2-Aminoalkoxylation of 1-Aryl-1,3-dienes by Dual Photoredox and Copper Catalysis, Org. Lett., 2022, 24, 7470–7475.
64. S. L. Rössler, B. J. Jelier, E. Magnier, G. Dagousset, E. M. Carreira and A. Togni, Pyridinium Salts as Redox-Active Functional Group Transfer Reagents, Angew. Chem., Int. Ed., 2020, 59, 9264–9280.
65. Y. Wang, Y. Bao, M. Tang, Z. Ye, Z. Yuan and G. Zhu, Recent advances in difunctionalization of alkenes using pyridinium salts as radical precursors, Chem. Commun., 2022, 58, 3847–3864.
66. G. Bertuzzi, A. Cerveri, L. Lombardi and M. Bandini, Tandem Functionalization-Carboxylation Reactions of π-Systems with CO, Chin. J. Chem., 2021, 39, 3116–3126.
67. J.-P. Yue, J.-C. Xu, H.-T. Luo, X.-W. Chen, H.-X. Song, Y. Deng, L. Yuan, J.-H. Ye and D.-G. Yu, Metallaphotoredox-enabled aminocarboxylation of alkenes with CO2, Nat. Catal., 2023, 6, 959–968.
68. S. Wang and C. Xi, Recent advances in nucleophile-triggered CO2-incorporated cyclization leading to heterocycles, Chem. Soc. Rev., 2019, 48, 382–404.
69. D. Louvel, A. Souibgui, A. Taponard, J. Rouillon, M. ben Mosbah, Y. Moussaoui, G. Pilet, L. Khrouz, C. Monnereau, J. C. Vantourout and A. Tlili, Tailoring the Reactivity of the Langlois Reagent and Styrenes with Cyanoarenes Organophotocatalysts under Visible-Light, Adv. Synth. Catal., 2022, 364, 139–148.
70. N. J. Venditto, Y. S. Liang, R. K. El Mokadem and D. A. Nicewicz, Ketone–Olefin Coupling of Aliphatic and Aromatic Carbonyls Catalyzed by Excited-State Acridine Radicals, J. Am. Chem. Soc., 2022, 144, 11888–11896.
71. J. Huang, Q. Gao, T. Zhong, S. Chen, W. Lin, J. Han and J. Xie, Photoinduced copper-catalyzed C–N coupling with trifluoromethylated arenes, Nat. Commun., 2023, 14, 8292.
72. J. M. Ahn, J. C. Peters and G. C. Fu, Design of a Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-Protected Primary Amines via Photoinduced, Copper-Catalyzed N-Alkylation Reactions of Unactivated Secondary Halides, J. Am. Chem. Soc., 2017, 139, 18101–18106.
73. J. Zhang, B. Xiong, X. Zhen and A. Zhang, Dopamine D1 receptor ligands: Where are we now and where are we going, Med. Res. Rev., 2009, 29, 272–294.
74. T. E. Müller and M. Beller, Metal-Initiated Amination of Alkenes and Alkynes, Chem. Rev., 1998, 98, 675–704.
75. D. Wang, L. Wu, F. Wang, X. Wan, P. Chen, Z. Lin and G. Liu, Asymmetric Copper-Catalyzed Intermolecular Aminoarylation of Styrenes: Efficient Access to Optical 2,2-Diarylethylamines, J. Am. Chem. Soc., 2017, 139, 6811–6814.
76. H.-Q. Do, E. R. R. Chandrashekar and G. C. Fu, Nickel/Bis(oxazoline)-Catalyzed Asymmetric Negishi Arylations of Racemic Secondary Benzylic Electrophiles to Generate Enantioenriched 1,1-Diarylalkanes, J. Am. Chem. Soc., 2013, 135, 16288–16291.
77. L. Wu, F. Wang, X. Wan, D. Wang, P. Chen and G. Liu, Asymmetric Cu-Catalyzed Intermolecular Trifluoromethylarylation of Styrenes: Enantioselective Arylation of Benzylic Radicals, J. Am. Chem. Soc., 2017, 139, 2904–2907.
78. R. López and C. Palomo, Cyanoalkylation: Alkylnitriles in Catalytic C–C Bond-Forming Reactions, Angew. Chem., Int. Ed., 2015, 54, 13170–13184.
79. J. Zhao, X. Liu, W. Luo, M. Xie, L. Lin and X. Feng, Asymmetric Synthesis of β-Amino Nitriles through a ScIII-Catalyzed Three-Component Mannich Reaction of Silyl Ketene Imines, Angew. Chem., Int. Ed., 2013, 52, 3473–3477.
80. T. M. Nguyen and D. A. Nicewicz, Anti-Markovnikov Hydroamination of Alkenes Catalyzed by an Organic Photoredox System, J. Am. Chem. Soc., 2013, 135, 9588–9591.
81. J. D. Griffin, C. L. Cavanaugh and D. A. Nicewicz, Reversing the Regioselectivity of Halofunctionalization Reactions through Cooperative Photoredox and Copper Catalysis, Angew. Chem., Int. Ed., 2017, 56, 2097–2100.
82. W. Zhang, F. Wang, S. D. McCann, D. Wang, P. Chen, S. S. Stahl and G. Liu, Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay, Science, 2016, 353, 1014–1018.
83. S. Qian, T. M. Lazarus and D. A. Nicewicz, Enantioselective Amino- and Oxycyanation of Alkenes via Organic Photoredox and Copper Catalysis, J. Am. Chem. Soc., 2023, 145, 18247–18252.

---

Footnote

† These authors contribute equally.

---