Carbonylation involving organocopper intermediates

Abstract

Developing economical and environmentally friendly carbonylation synthetic methods is an important and challenging goal. Exploring the application of non-precious metal catalysts in synthetic chemistry has proven to be an ideal choice due to their abundancy, low cost, and low toxicity. In recent years, as copper is one of the cheaper metals, copper catalysts have been widely used in the field of carbonylative transformations. In this review, case-by-case reaction modes and mechanisms are summarized and discussed, along with a personal perspective. Various organocopper intermediates were produced from the single-electron reduction of alkyl halides, capturing radicals from the oxidation of carbon-hydrogen bonds, transmetalation, and active copper species addition to unsaturated bonds (active Cu–H, Cu–Bpin or Cu–Si intermediate), and then, different organocopper intermediates can result from nucleophilic quenching, electrophilic quenching, transmetalation, isomerization to carbene, etc.

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Zhi-Peng Bao

Zhi-Peng Bao was born in Anhui, China, in 1996. He received his MS degree in 2021 from Zhejiang Sci-Tech University. He is currently pursuing his PhD degree in a joint training program at the Leibniz Institute for Catalysis (Germany) and the Dalian Institute of Chemical Physics (DICP) under the supervision of Prof. Xiao-Feng Wu. His current research interests focus on the palladium-catalyzed carbonylation of activated alkyl halides.

Xiao-Feng Wu

Xiao-Feng Wu was born and raised in China. After being educated and trained at China (Zhejiang Sci-Tech University), France (Rennes 1 University) and Germany (Leibniz-Institute for Catalysis), he started his independent research at LIKAT and ZSTU, where he was promoted to professor in 2013. Afterwards, he defended his Habilitation from Rennes 1 University (2017). In 2020, he joined the Dalian Institute of Chemical Physics (DICP) and established a research group focusing on light carbon transformation and practical synthesis. Xiao-Feng Wu has authored more than 660 publications, edited more than 10 books and filed many patents. He has also been honored with various awards.

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Broader context

Carbonylative transformation is an important strategy for the preparation of carbonylated compounds with CO as the C1 source. This methodology is usually catalysed by expensive noble metal catalysts. Copper catalysts have been explored as an alternative because of its low cost and to further advance the understanding of catalyst design. In this review, case-by-case reaction modes and mechanisms are summarized and discussed, along with a personal perspective. Various organocopper intermediates were produced from the single-electron reduction of alkyl halides, capturing radical from the oxidation of carbon–hydrogen bonds, transmetalation, and active copper species addition to unsaturated bonds (active Cu–H, Cu–Bpin or Cu–Si intermediate), and then, different organocopper intermediates can result from nucleophilic quenching, electrophilic quenching, transmetalation, isomerization to carbene, etc. This review will inspire the further development of carbonylation chemistry.

1. Introduction

Carbonyl-containing compounds are widely present in natural products, pharmaceuticals, agrochemicals, and polymers.¹ As a versatile functional group, the carbonyl moiety can undergo diverse transformations to easily increase molecular complexity, offering a valuable platform for synthetic chemistry.² According to FDA statistics from 2015 to 2020, approximately 80% of approved drugs contain carbonyl functional groups.³ For instance, Eliquis (ranked second in 2024 retail drug sales for thrombosis prevention) and Revlimid (ranked 28th for multiple myeloma treatment) each contain three or more carbonyl groups, with market values of $20.699 billion and $5.809 billion, respectively.⁴ In synthetic chemistry, carbonylation technologies provide one of the most efficient and atom-economical methods for constructing carbonyl compounds.⁵ These processes convert carbon monoxide—derived from coal, natural gas, or biomass—into value-added carbonylated products with 100% atom utilization.⁶ One of the most renowned examples is the carbonylation of methanol to produce acetic acid, as exemplified by the Monsanto and Cativa processes.^7,8 Notably, a majority of the world's acetic acid is currently produced via methanol carbonylation.⁹ Another valuable application is the synthesis of methyl methacrylate (MMA), a key monomer for the production of poly(methyl methacrylate) (PMMA), with a global annual production of approximately 4 million tons.¹⁰ Among current technologies, ethylene carbonylation has emerged as one of the most attractive methods due to its high cost-effectiveness and excellent atom economy.¹¹

In the historical development of carbonylation technologies, palladium-catalyzed carbonylation has emerged as one of the most mature and well-established systems.¹² As early as 1974, the Heck group reported the first palladium-catalyzed carbonylation of aryl halides and benzyl halogenated compounds.¹³ Later, Ryu and co-workers presented their pioneering study on the free-radical-mediated carbonylation of unactivated alkyl halides.¹⁴ Since then, Pd–H catalytic systems have witnessed explosive growth.^15–25 A remarkable example was reported in 2019 by the Beller group, who designed a series of original pyridyl-substituted bidentate phosphine ligands to achieve the highly efficient synthesis of the nylon-66 monomer via double carbonylation of 1,3-butadiene, successfully addressing a long-standing scientific challenge that had persisted for nearly a century (Fig. 1).²⁶

Fig. 1 Importance of carbonyl-containing molecules and diverse reaction modes in carbonylation chemistry by Pd or Cu catalysis.

In the past decade, copper-catalyzed carbonylation systems have flourished, paralleling the rapid progress seen in palladium-catalyzed carbonylation.²⁷ These copper-based systems exhibit greater diversity in reaction modes. As a cheap and earth-abundant 3d transition metal—with an estimated crustal abundance of approximately 0.01%—copper has attracted significant interest from the chemical community. Numerous copper-catalyzed carbonylation reactions have been developed. In this work, we categorize these transformations based on their mechanistic features, particularly focusing on the formation and subsequent quenching of organocopper intermediates (Fig. 2). This mechanistic framework facilitates a deeper understanding for readers and may inspire exploration into new areas of chemical space. Overall, these carbonylation pathways can be broadly divided into four types: (I) single-electron reduction processes of organic halides and related compounds; (II) radical capture from the HAT process and other routes; (III) addition of reactive copper species (Cu–H, Cu–Bpin, Cu–[Si], etc.) to unsaturated bonds; (IV) transmetalation pathways.

Fig. 2 Diverse types of single-electron reduction processes of organic halides.

2. Single electron reduction of organic halides

The single-electron reduction of organic halides typically involves activation of C(sp³)–X and N–X bonds. This strategy utilizes a single-electron transfer (SET) process to generate carbon-centered radicals, which then engage in subsequent additions to metal species or carbon monoxide, ultimately forming acyl copper intermediates. These intermediates can undergo either nucleophilic trapping or direct reductive elimination to afford the final products. This reaction mode can be broadly categorized into four types: (1) the carbon radical generated via a SET process directly captures CO, followed by nucleophilic trapping to afford amides, esters, or acyl fluorides; (2) a reactive copper species initiates the SET activation of alkyl halides, leading to the formation of acyl copper intermediates, which subsequently undergo reductive elimination to give acylboronates, acylsilanes, aldehyde intermediates, or other products; (3) a reactive copper species facilitates the addition of unsaturated bonds, and then, the SET process takes place; (4) in radical relay processes, a carbon radical is first added to alkenes, generating a new radical that is captured by a copper catalyst. CO is then incorporated either through radical addition or metal coordination, forming an acyl copper intermediate that is ultimately quenched by nucleophiles.

2.1 Nucleophilic quenching of organocopper intermediates

The capture of CO by carbon radicals generated via the single-electron reduction of alkyl halides can proceed through different pathways, depending on the mode of quenching and the nature of the nucleophile. These variations will be discussed in detail below. In 2022, our group developed a copper-catalyzed, substrate-controlled mono- and double-carbonylation strategy that efficiently converted alkyl halides and amines into α-ketoamides and amides.²⁸ This method exhibits excellent selectivity for alkyl bromides, exclusively affording the double-carbonylated products. In contrast, alkyl iodides allow for selective control between mono- and double-carbonylation under specific conditions. As illustrated in Fig. 3, the reaction begins with the coordination of CO to the copper salt, forming a Cu–(CO) species (3-B). In the presence of a base, a nucleophilic attack by the amine on the coordinated CO generates intermediate 3-C. Alternatively, the amine may undergo anionic ligand exchange with 3-B to yield an aminocopper(I) species (3-C′). These intermediates (3-C or 3-C′) then participate in a single-electron reduction of the alkyl bromide, leading to the formation of a radical intermediate and 3-D, and an acyl radical intermediate is given under a CO atmosphere. Then, the acyl radical reacts with 3-D to form the key intermediate 3-E, which undergoes reductive elimination to release the α-ketoamide product and regenerate the catalyst 3-A. On the other hand, due to the higher reactivity of alkyl iodides compared to bromides, activation of the alkyl iodide may occur prior to nucleophilic attack by the amine, resulting in intermediate 3-F. This species reacts with the acyl radical to form intermediate 3-G. In the presence of a base, anionic ligand exchange on copper generates intermediate 3-H, which undergoes reductive elimination to afford the amide product and regenerate catalyst 3-B. Additionally, nucleophilic attack of the amine on coordinated CO in 3-G may occur, forming intermediate 3-E and leading to the α-ketoamide as a competing product.

Fig. 3 Copper-catalyzed direct mono- and double-carbonylation reactions.

Anhydrides play a significant industrial role due to their wide applications in the synthesis of polymers, pharmaceuticals, and other commodity chemicals.²⁹ For example, acetic anhydride (Ac₂O) is especially critical in the wood industry, where its hydrophobic nature makes it an effective protective coating.³⁰ Therefore, developing convenient and efficient methods for synthesizing commodity anhydrides is of great interest. However, traditional synthetic routes often involve multiple steps and rely on precious metal catalysts. Acetic anhydride is currently produced on an industrial scale via a two-step rhodium-catalyzed carbonylation technique, and is widely used in the synthesis of important products like aspirin.³¹ In 2023, Mankad reported a copper-catalyzed carbonylation of alkyl halides to aliphatic anhydrides via a single-electron transfer (SET) mechanism.³² The proposed mechanism is illustrated in Fig. 4. Under 390 nm light irradiation, the copper catalyst 4-A absorbs a photon to generate the excited state 4-B. This excited [Cu]* species possesses sufficient reducing power to engage in SET with alkyl halides, producing intermediate 4-C and an alkyl radical. The alkyl radical then reacts with CO to afford an acyl radical. The combination of 4-C with the acyl radical yields intermediate 4-D, which undergoes reductive elimination to furnish the corresponding acyl halide. Subsequently, the acyl halide reacts with K₂CO₃, undergoing decarboxylation to generate a carboxylate species. Finally, condensation between the carboxylate and acyl halide results in the formation of the corresponding anhydride product.

Fig. 4 Copper-catalyzed direct carbonylation for the synthesis of the anhydrides.

In 2024, the same group reported a copper-catalyzed carbonylation for the synthesis of acyl fluorides.³³ It is similar to the mechanism proposed above, as this transformation also proceeds via a single-electron reduction pathway. However, the key difference lies in the quenching step, where a fluoride anion is employed as the nucleophile (Fig. 5).

Fig. 5 Copper-catalyzed direct carbonylation for the synthesis of the acyl fluorides.

In addition to the novel copper-catalyzed carbonylation pathways of alkyl iodide and alkyl bromide proceeding via SET processes described above, other reaction routes have been developed. For example, alkyl fluorides can be transformed into alkyl iodides through halogen exchange, followed by a similar SET-based carbonylation mechanism.³⁴ Alternatively, the nucleophile in the quenching step can be replaced with alcohols,^35–38 nitroarenes,³⁹ arylboronic acids⁴⁰ and others,^41–43 to access a broader range of carbonyl-containing products (Fig. 6).

Fig. 6 Other examples of the SET process of organic halides towards carbonyl compounds.

2.2 Active copper species-mediated SET process of halides (direct elimination)

In recent years, active copper species have found widespread applications in organic catalysis. Key reactive intermediates include Cu–Bpin, Cu–[Si], and Cu–H, each of which exhibits distinct reactivity profiles. These species have also demonstrated unique modes of reactivity in the field of carbonylation chemistry. In the following sections, we will discuss carbonylation processes mediated by active copper species, particularly those involving single-electron reduction.

In 2020, the Mankad group developed a novel copper-catalyzed carbonylative silylation of organic halides.⁴⁴ The proposed mechanism is illustrated in Fig. 7. Initially, in the presence of a base, PhMe₂Si–Bpin undergoes transmetallation with the copper(I) species 7-A to form a silyl–copper(I) complex 7-B. Subsequently, 7-B engages in a single-electron reduction with the alkyl halide, generating the corresponding alkyl radical (R˙) and intermediate 7-C. Under a CO atmosphere, the alkyl radical is rapidly converted into an acyl radical, which then combines with intermediate 7-C to form the acyl copper species 7-D, which is coordinated with a silicon-containing ligand. This is due to the reactivity of the acyl radical being higher under this condition. Finally, 7-D undergoes reductive elimination to give the corresponding acylsilane product, regenerating the active copper(I) catalyst 7-A.

Fig. 7 Copper–silyl intermediate-mediated carbonylation toward acylsilane derivatives.

In 2021, Mankad and co-workers developed an interesting copper-catalyzed carbonylative borylation of organic halides.⁴⁵ The proposed mechanism is illustrated in Fig. 8. Initially, in the presence of a base, B₂pin₂ undergoes transmetallation with the copper(I) catalyst 8-A to form an active Cu(I)–Bpin species 8-B. Subsequently, 8-B engages in a single-electron reduction of the alkyl halide, generating an alkyl radical (R˙) and the Cu(II) species 8-C. Under a CO atmosphere, the alkyl radical rapidly captures CO to form an acyl radical, which then couples with intermediate 8-C to afford the acyl–copper intermediate 8-D, coordinated with a Bpin group. Reductive elimination from 8-D, followed by post-reaction treatment, yields aliphatic potassium acyltrifluoroborates, while regenerating the active copper(I) catalyst 8-A. An alternative pathway for radical generation may also be involved: LiOtBu reacts with B₂pin₂ to generate a reactive intermediate 8-E, which can reduce the alkyl halide via the SET process to form the corresponding alkyl radical. It is worth noting that the intermediate R–CO–Bpin is not stable under these reaction conditions, and thus requires appropriate post-treatment for successful detection of the product.

Fig. 8 Carbonylative transformation involving Cu–Bpin intermediates toward acylboron derivatives.

In addition to Cu–Si and Cu–Bpin intermediates, Cu–H species have emerged as a focal point in carbonylation chemistry. As early as 2018, the Mankad group reported a copper-catalyzed hydroxymethylation of unactivated alkyl iodides.⁴⁶ Later, in 2021, Wu and co-workers developed a borylative methylation process that simultaneously employed both Cu–Bpin and Cu–H intermediates.⁴⁷ In this catalytic system, the reaction between Cu–H and alkyl iodides proceeds faster than that with Cu–Bpin. A more detailed mechanistic pathway is illustrated as follows: first, in the presence of a silane, the copper catalyst 9-A reacts to form a Cu–H species 9-B. This Cu–H species undergoes single-electron reduction of the alkyl iodide, generating a carbon-centered radical and the intermediate 9-C. Under a CO atmosphere, the carbon radical rapidly captures CO to form an acyl radical, which then couples with 9-C to afford the acyl-copper intermediate 9-D. Reductive elimination from 9-D gives either an acyl halide or an aldehyde, along with regeneration of the active copper species 9-A or 9-B. The resulting acyl halide can be further reduced by Cu–H to yield the corresponding aldehyde. This aldehyde may then undergo further transformations, including reduction to one-carbon-extended alcohols, borylmethylation to borane compounds, or diborylmethylation to give diborane derivatives (Fig. 9).

Fig. 9 Carbonylative transformation of alkyl iodides involving Cu–H intermediates.

2.3 Addition of unsaturated bonds, then SET process (electrophilic quenching)

Active copper species made their first appearance in carbonylation chemistry in 2017, when Mankad and co-workers reported on the copper-catalyzed hydrocarbonylation of terminal alkynes for the synthesis of unsymmetrical dialkyl ketones and allylic alcohol derivatives.^48,49 By controlling the reaction temperature, they further achieved either 1,4- or 1,2-addition of Cu–H species to the resulting enone intermediate, leading to two distinct types of products. As illustrated in Fig. 10, IPrCuCl first reacts with a base to form IPrCuOMe, which then undergoes transmetallation with a silane to generate the active Cu–H species 10-A. This species adds across the terminal alkyne to give the alkenyl copper intermediate 10-B. Subsequently, 10-B engages in a single-electron reduction of the alkyl iodide, forming intermediate 10-C and an alkyl radical. In the presence of CO, the alkyl radical rapidly adds CO to form an acyl radical, which then combines with 10-C to afford the Cu(III) intermediate 10-D. Reductive elimination from 10-D yields the α,β-unsaturated ketone 10-E and regenerates the Cu(I) catalyst, which re-enters the catalytic cycle via reaction with a base and silane to form IPrCuH. The enone 10-E then undergoes further functionalization. At 60 °C, it undergoes 1,4-addition with Cu–H, followed by silane quenching to afford unsymmetrical dialkyl ketones. Alternatively, at room temperature, 10-E undergoes 1,2-addition with Cu–H, and subsequent quenching with silane gives allylic alcohol derivatives.

Fig. 10 Copper-catalyzed hydrocarbonylative coupling of alkynes (CuH addition to alkynes).

Following CuH-mediated hydrocarbonylation, copper-catalyzed borocarbonylative couplings of alkynes and alkenes have also been reported.^50,51 As illustrated in Fig. 11, the reaction begins with the generation of a (L)CuOMe complex via the reaction of a Cu(I) catalyst with a base and ligand. This complex then undergoes transmetallation with B₂pin₂ to form the active (L)CuBpin species 11-A. Next, the (L)CuBpin complex is inserted into the unsaturated bond of an alkyne or alkene, affording the organocopper intermediate 11-B. Intermediate 11-B then undergoes single-electron reduction of an alkyl iodide to generate intermediate 11-C and an alkyl radical. Under a CO atmosphere, the alkyl radical is rapidly converted into an acyl radical, which subsequently couples with 11-C to form intermediate 11-D. Reductive elimination from 11-D obtains boryl ketone derivatives and regenerates the Cu(I) catalyst. Then, the active (L)Cu–Bpin species 11-A is regenerated via ligand exchange with a base and B₂pin₂, thus completing the catalytic cycle.

Fig. 11 Copper-catalyzed borocarbonylative coupling of alkynes and alkenes (CuBpin addition to alkynes and alkenes).

The selective control of catalytic transformation has attracted the attention of organic synthetic chemists, and has become a long-term goal in synthetic chemistry.⁵² Among the four fundamental types of selectivity, regioselectivity—which governs the positional outcome of reactions near the reactive site—has been an active area of research in carbonylation chemistry. For example, in the palladium-catalyzed carbonylation of alkenes or alkynes, the selectivity between linear and branched products can be finely tuned using monodentate and bidentate phosphine ligands,⁵³ and we can influence N- versus O-nucleophilic selectivity by the electronic and steric properties of ligands and bases,⁵⁴ or the choice of solvent (Fig. 12 and 13).⁵⁵

Fig. 12 Phosphine and NHC ligands modulate the formation of organocopper intermediates in the carbonylation chemistry.

Fig. 13 Diverse copper-catalyzed carbonylation reactions enabled by the radical relay mechanism.

However, regioselective examples in copper-catalyzed carbonylation reactions remain scarce. Moreover, the reported unsaturated substrates are almost exclusively limited to alkenes and alkynes, and there are few examples for regioselective carbonylation of imines. This scarcity is attributed to the intrinsic electronic polarization of the C=N bond, which places a partial positive charge on the carbon position, rendering it electrophilic and thus prone to nucleophilic attack. This intrinsic polarization makes it challenging to achieve controlled and selective addition.⁵⁶

In 2019, the Hou group reported an intriguing example involving the intramolecular 1,2-migration of a boryl group from carbon to nitrogen in imines.⁵⁷ However, regioselectivity in this transformation remained difficult to control. In 2021, Wu and co-workers reported a pioneering example of regioselective carbonylation of imines via copper catalysis.⁵⁸ The detailed reaction mechanism is illustrated as follows: initially, the LCu–Bpin species 12-B is generated from 12-A, B₂pin₂, and a base, and is subsequently inserted into the C=N bond of the imine to form intermediate 12-C. In the presence of electron-deficient ligands, the N–Cu bond in 12-C is relatively weak, favoring an intramolecular 1,2-migration to yield intermediate 12-F. This rearrangement is likely driven by the formation of a strong B–N bond. Alternatively, it is also possible that 12-F is directly formed via the reaction between 12-B and the imine. Next, 12-F undergoes a single-electron process with an alkyl iodide to give intermediate 12-G. Coordination of CO to 12-G, followed by migratory insertion, yields the acyl copper species 12-H. Reductive elimination and subsequent methanol quenching afford the corresponding α-aminoketone product, while regenerating 12-A to re-enter the catalytic cycle. In a parallel catalytic pathway, under the influence of a carbene ligand, the electron-rich copper intermediate 12-C can directly engage in a single-electron transfer with an alkyl iodide to form intermediate 12-D. After CO insertion, 12-E is formed, which undergoes reductive elimination to deliver an alternative product-an α-borylamide.

2.4 Radical relay

Multicomponent reactions (MCRs), which combine three or more reactants in one reaction vessel to produce a single major product, represent an efficient and valuable strategy for constructing highly functionalized molecules from readily available building blocks.⁵⁹ Copper-catalyzed radical relay carbonylation reactions constitute a class of four-component transformations involving diverse radical precursors, alkenes, carbon monoxide, and nucleophiles. Representative radical precursors include fluoroalkyl sources such as Togni II reagents⁶⁰ or perfluoroalkyl halides,⁶¹ nitrogen-centered radical precursors such as RR¹N–OBz,⁶² trichloromethyl radical precursors such as carbon tetrachloride,⁶³ and others.^64,65

Initially, the copper catalyst undergoes single-electron reduction of the radical precursor to generate the corresponding radical and the Cu(II) intermediate 13-B. The radical is then added to an alkene, forming a new carbon-centered radical. This radical intermediate can recombine with 13-B to generate an alkyl–copper(III) intermediate 13-C, and it can also capture CO to give acyl radical 13-F. Subsequent CO coordination affords the carbonylated Cu(III) complex 13-D, which also can be formed from the acyl radical and 13-B. Migratory insertion of CO yields intermediate 13-E, which then undergoes reductive elimination in the presence of a nucleophile to deliver the final product, regenerating the Cu(I) catalyst. Notably, when the electronic nature of the radical precursor and alkene are mismatched, additives are often required. For example, activation of nitrogen-centered radical precursors may require the use of Lewis acids, which help modulate reactivity and enable the polarity-reversed addition of nucleophilic amino radicals to electron-rich alkenes.

In 2022, the Wu group developed a copper-catalyzed 1,2-dicarbonylative cyclization of alkenes via radical relay.⁶⁶ As illustrated in Fig. 14, this transformation represents a novel type of carbonylation reaction via a radical relay pathway. Initially, the alkyl bromide undergoes a single-electron transfer (SET) with a copper catalyst to generate an alkyl radical 14-A. This radical is then captured by carbon monoxide to form an acyl radical 14-B. Subsequently, 14-B is added to an unactivated alkene, forming a new carbon-centered radical 14-C. Then, a second CO molecule is incorporated by 14-C, yielding another acyl radical intermediate 14-D. This newly formed acyl radical undergoes electrophilic addition to an arene to 14-E, followed by oxidation and rearomatization through deprotonation to deliver the final product. This transformation thus establishes a novel carbonylation strategy for the construction of 1,4-diketones via a radical cascade process.

Fig. 14 Copper-catalyzed 1,2-dicarbonylative cyclization of alkenes via radical relay.

In summary, in the transformations of single electron reduction of organic halides, the reduction potential needs to be below −2 V compared to the saturated calomel electrode (SCE) for unactivated alkyl iodides; the reducing power of the copper catalyst can be enhanced by photoexcitation or by employing appropriate ligands. In addition, activated alkyl halides are more easily reduced than inactivated alkyl halides, and unactivated alkyl radicals tend to capture CO while activated alkyl radicals tend to add to alkenes. In our view, the active copper species-mediated single electron reduction of halides to acylsilane or R–CO–Bpin is a novel reaction mode compared to other metal catalysis in carbonylation chemistry.

3. Radical capture to form organocopper intermediates (HAT process and others)

The hydrogen atom transfer (HAT) process has found wide application in organic methodology. Common hydrogen abstractors include peroxides,⁶⁷ sodium decatungstate,⁶⁸ and specially designed nitrogen-centered radical precursors.⁶⁹ In recent years, the HAT tool has also emerged as a growing area of interest in carbonylation chemistry, with copper-, cobalt-, and nickel-catalyzed carbonylation reactions with the HAT process being actively explored.^11,70–73

In 2016, Wu and co-workers developed a copper-catalyzed carbonylative coupling of cycloalkanes.^74,75 The proposed mechanism is illustrated in Fig. 15. The reaction begins with the thermal homolysis of di-tert-butyl peroxide (DTBP), generating tert-butoxy radicals. These radicals undergo hydrogen atom transfer (HAT) with alkanes to form carbon-centered radicals. The resulting radicals are then captured by 15-A to generate Cu(III)–alkyl intermediates (15-B). Intermediate 15-B subsequently reacts with an amine to form 15-C, which undergoes CO insertion to give intermediates 15-D or 15-E. These species then undergo reductive elimination to produce the carbonylated product and regenerate Cu(I) 15-F. Finally, Cu(I) is reoxidized to 15-A, completing the catalytic cycle. Notably, this work represents the first report of copper-catalyzed carbonylation via C–H activation.

Fig. 15 Radical capture via HAT process towards esters or amides.

In the copper-catalyzed double carbonylation transformation (Fig. 16),⁷⁶ di-tert-butyl peroxide (DTBP) also undergoes thermal homolysis to generate tert-butoxy radicals. These radicals can abstract a hydrogen atom from either amines or alkanes via a hydrogen atom transfer (HAT) process, leading to the formation of carbon-centered or nitrogen-centered radicals. Upon capturing CO, these radicals are converted into the corresponding acyl or amide radicals. Based on control experiments, the authors proposed that in some cases, the acyl radical may further capture a second molecule of CO to generate an α-ketoacyl radical.

Fig. 16 Radical capture via HAT process toward dicarbonylated products.

The proposed catalytic cycle proceeds as follows: the alkyl radical is first intercepted by Cu(I) to form intermediate 16-B, which upon CO coordination yields the alkyl acyl–copper intermediate 16-C. Alternatively, 16-C may be formed by direct capture of an acyl radical by Cu(I). Subsequent capture of an acyl radical by 16-C furnishes the intermediate 16-D. An alternative pathway involves the α-ketoacyl radical being trapped by 16-B to form the same intermediate 16-D. Finally, it undergoes reductive elimination to deliver the double-carbonylated product and regenerate the active Cu(I) catalyst 16-A.

In our group's first report on copper-catalyzed carbonylation via C–H activation, we serendipitously discovered a new reaction pathway involving β-scission of a radical intermediate to generate a methyl radical. The resulting methyl radical is then captured by the copper catalyst and CO to form an acyl–copper intermediate. Subsequent reductive elimination delivers the carbonylated product and regenerates the Cu(I) catalyst, as illustrated in Fig. 17.⁷⁷

Fig. 17 Radical capture via β-scission toward acetamide derivatives.

In this Cu-catalyzed carbonylation of acetonitrile via radical cascade process,⁷⁸ the reaction is initiated by the thermal homolysis of di-tert-butyl peroxide (DTBP), generating tert-butoxy radicals. These radicals abstract a hydrogen atom from acetonitrile via a hydrogen atom transfer (HAT) process to form a cyano-containing alkyl radical, which is subsequently added to an unactivated alkene to generate a new carbon-centered radical. This radical is then captured by 18-A to form intermediate 18-B. Following an anionic ligand exchange with a nucleophile, intermediate 18-C is formed. Under a CO atmosphere, 18-C undergoes CO insertion to give either intermediate 18-D or 18-E. Reductive elimination then affords the desired product along with a Cu(I) species (18-F), which is reoxidized by DTBP to regenerate 18-A. This transformation exemplifies a copper-catalyzed strategy that merges the HAT process and radical relay pathways (Fig. 18).

Fig. 18 Radical capture via radical cascade process.

4. Active copper species addition (except SET process)

4.1 Acyl copper intermediates isomerization to carbene species

In the past five years, Wu and co-workers have reported a series of copper-catalyzed carbonylation reactions involving carbene intermediates. These transformations enable the conversion of carbon monoxide into aldehydes, alcohols, methylene (–CH₂–), and –CH₂CO– motifs, offering new paradigms for carbonylation chemistry and significantly expanding the toolbox of copper catalysis. An overview of these reaction pathways is illustrated in Fig. 19.

Fig. 19 Isomerization of organocopper intermediates to a carbene species in carbonylation chemistry.

Currently, two major classes of reactive copper intermediates have been identified: Cu–H and Cu–Bpin species. The LCu–H intermediate (19-A) is generated via transmetalation from copper catalysts, hydrogen gas, and base. This species captures CO to form an acyl copper intermediate 19-B, which undergoes isomerization to generate an α-oxy carbene intermediate. The resulting carbene can then undergo either H₂ insertion via cleavage of the H–H bond or α-C–H insertion. The former leads to intermediate 19-E, which upon protonation gives alcohol derivatives; the latter obtains intermediate 19-D, which is further protonated and isomerized to afford aldehyde derivatives.⁷⁹

The second pathway involves the Cu–Bpin intermediate 19-F, formed via transmetalation from a copper catalyst, B₂Pin₂, and base. Upon trapping CO, 19-F gives rise to the acyl-copper intermediate 19-G, which can similarly isomerize into a carbene species 19-H. This intermediate has been more extensively developed in carbonylation chemistry, enabling transformations such as β-C–H insertion (19-I),⁸⁰ further CO capture (19-J),^81,82 α-C–H insertion (19-K),⁸³ O–H insertion (19-L),⁸⁴ alkene capture (19-M),⁸⁵ and N–H insertion (19-N).⁸⁶ These transformations produce structurally diverse carbonyl- or CH₂-containing organoboron compounds, which can be further diversified through downstream modifications such as vinylation, reduction, oxidation, halogenation, or Suzuki–Miyaura cross-coupling.

In summary, copper-catalyzed carbonylation reactions involving carbene intermediates operate through unique catalytic cycles based on low-valent copper species. Unlike conventional metal-catalyzed transformations, these reactions do not involve oxidative addition, reductive elimination, or single-electron transfer (SET) processes. While this approach offers novel reactivity, it still faces several limitations: for instance, the reaction typically requires alkene addition to initiate the catalytic cycle, limiting the initiation mode; CuH-based carbene transformations remain underdeveloped; and carbene routes involving Cu–[Si] species have not yet been realized. Moreover, mechanistic insights via DFT calculations could provide valuable validation and guidance for further development.

4.2 Organocopper intermediates coordinated with chiral ligands (Cu–Bpin and Cu–H species)

Chiral carbonyl-containing compounds play a vital role in medicinal chemistry, and carbonylation has emerged as an efficient and valuable strategy for their construction.⁸⁷ For example, BHC's industrial production of ibuprofen involves only three steps and achieves an atom economy of up to 77 percent. The final product is obtained as a racemate, and is widely used as an anti-inflammatory and analgesic agent. Although both enantiomers exhibit similar pharmacological properties, the (S)-enantiomer is 28 times more active than the (R)-enantiomer. This discrepancy has also prompted strong interest in the development of efficient asymmetric carbonylation technologies. Notable examples include asymmetric carbonylation reactions developed by the Liao and Shi groups, which predominantly rely on palladium catalysis.^88,89 However, due to the high cost of palladium, the development of asymmetric carbonylation methods based on earth-abundant metals such as copper is highly desirable. In 2020, the Wu group reported the first copper-catalyzed asymmetric carbonylation of aryl alkenes, affording chiral α-amides (20-A).⁹⁰ In 2023, they extended this methodology to alkyl alkenes, enabling the synthesis of chiral β-amides (20-B).⁹¹ In 2024, they further developed an asymmetric reductive relay hydroaminocarbonylation strategy to access chiral γ-amides (20-C),⁹² and in the same year, achieved asymmetric carbonylation of internal alkenes to furnish 20-D.⁹³ In 2025, chiral α,β-unsaturated ketone derivatives were also synthesized via copper catalysis.⁹⁴ In addition to the CuH-mediated catalytic cycles, Cu–Bpin species have been employed in asymmetric carbonylation reactions.⁹⁵ The utilization of chiral ligands and specific reaction conditions are detailed in Fig. 20.

Fig. 20 Organocopper intermediates in the asymmetric carbonylative reaction (Cu–H and Cu–Bpin species addition to alkenes).

In summary, copper-catalyzed asymmetric carbonylation remains an emerging field, but recent advances have demonstrated excellent levels of chemo- and stereoselectivity. Our group is actively working on the development of new copper-catalyzed asymmetric carbonylation methodologies to further expand the scope and applicability of this promising strategy.

5. Transmetalation

5.1 Transmetalation towards organocopper intermediates

Transmetalation is a fundamental step in organometallic catalysis and has been widely applied in numerous cross-coupling reactions, such as the Suzuki–Miyaura coupling (boron),⁹⁶ Stille coupling (tin),⁹⁷ Kumada coupling (magnesium),⁹⁸ and others. As early as 1996, Kang and co-workers reported a copper-catalyzed carbonylative Stille-type coupling reaction between organostannanes and hypervalent iodine salts.⁹⁹ In this transformation, transmetalation from tin to copper generated organocopper intermediates, which subsequently underwent carbonylation.¹⁰⁰ Since then, copper-catalyzed carbonylation reactions involving arylboronic acids with aryl iodides or alkyl halides have also been developed.^101,102 In these systems, aryl iodides tend to undergo carbonylation via a two-electron oxidative addition pathway, whereas alkyl halides tend to follow a single-electron transfer (SET) mechanism (Fig. 21).

Fig. 21 Carbonylation initiated by transmetalation.

5.2 Organocopper intermediates take transmetalation to diverse metal catalysts (Pd, Fe)

In the field of metal-catalyzed organic methodology, cooperative catalysis represents a form of multiple catalysis system that employs at least two distinct catalysts to enable reactions between two separately activated substrates. This approach has unlocked a plethora of previously unattainable transformations and novel chemical reactions. In carbonylation reactions involving organocopper intermediates, as summarized in Fig. 22, copper–palladium cooperative catalysis exemplifies this strategy-for instance, the transmetalation of alkynylcopper intermediates with acylpalladium species to afford alkynone derivatives 22-A.¹⁰³ For example, after the addition of Cu–Bpin to unsaturated bonds, the resulting organocopper intermediate undergoes transmetalation with acylpalladium species, leading to the formation of boron-containing ketone compounds 22-B.^104–107 In addition to copper-to-palladium transmetalation, copper-to-manganese transmetalation affords ketone compounds 22-C,¹⁰¹ while copper-to-iron transmetalation yields ester derivatives 22-D.¹⁰⁸

Fig. 22 Transmetalation of organocopper intermediates into other metal catalysts.

6. Others

In the developmental course of copper-catalyzed carbonylation reactions, there remain certain transformations that are still in their infancy and have not yet formed a unified reaction system, or reactions that require further development and exploration. This is entirely reasonable, so they are included in this section for contemplation and discussion.

As illustrated in Fig. 23, in 2009, the Xia group reported an intriguing example of the double carbonylation of aromatic iodides and amines. This conversion proceeded under mild conditions with good functional group tolerance. However, the reaction mechanism remains to be elucidated, and the reaction necessitates the addition of an excess of carbene ligand.¹⁰⁹

Fig. 23 Copper-catalyzed double carbonylation of aryl iodides and amines.

In the developmental landscape of copper-catalyzed carbonylation reactions, the capture of carbene intermediates by copper catalysts represents a fascinating transformation. In 2023, Wu and co-workers reported a copper-catalyzed carbonylation of carbenes distinguished by exceptional functional group tolerance and chemoselectivity.¹¹⁰ The proposed mechanistic pathway is delineated in Fig. 24. Initially, under a carbon monoxide atmosphere, the active copper catalyst 24-A coordinates with CO to generate intermediate 24-B. Subsequently, the diazo compound engages in the reaction, yielding the copper–carbene intermediate 24-C with the concomitant release of nitrogen. Through the insertion of CO, this intermediate is converted into the ketene intermediate 24-D. Finally, nucleophilic attack, coupled with the liberation of the active copper complex 24-A for subsequent catalytic cycles, furnishes the corresponding product.

Fig. 24 Copper-catalyzed direct carbonylation of carbenes.

In the realm of double carbonylation reactions, reports leveraging alcohols as nucleophiles to afford corresponding α-ketoester derivatives remain relatively scarce. In 2018, employing hexaketocyclohexane octahydrate as the carbonyl source, Wang and co-workers reported on a novel paradigm of copper-catalyzed double carbonylation of indoles with alcohols.¹¹¹ Noteworthily, while hexaketocyclohexane octahydrate generates CO gas under standard conditions, the product yield plummets to below 5% when using gaseous CO, rendering this transformation a distinctive case of oxidative carbonylation. Despite its synthetic potential, the mechanistic intricacies of this protocol warrant in-depth investigation, given the unique reactivity profile of the solid-state carbonyl source and the stark disparity in reaction efficiency compared to conventional CO gas systems (Fig. 25).

Fig. 25 Copper-catalyzed double carbonylation of indoles and alcohols.

7. Conclusion and outlook

Given the extensive applications of carbonyl-containing compounds in pharmaceuticals, agrochemicals, and materials science, the development of cost-effective catalytic systems for the rapid construction of such motifs is of paramount importance. Among contemporary carbonylation technologies, palladium-catalyzed methods and copper-catalyzed methodologies have emerged as two of the most prominent strategies. In the past decades, carbonylation reactions involving organocopper intermediates have witnessed rapid and vigorous development, paralleling advances in palladium catalysis and even surpassing it in terms of reaction diversity, owing to the burgeoning array of novel catalytic modes enabled by copper. These include single-electron reduction of organic halides, radical-trapping mechanisms, addition of reactive copper species to unsaturated bonds, asymmetric catalysis using chiral ligands, copper-mediated radical relay reactions, isomerization of acylcopper species to α-oxy carbene intermediates, and transmetalation processes, etc. Notably, certain reaction classes, such as the addition of reactive copper species to unsaturated bonds, not only exhibit chemoselectivity but also regioselectivity, allowing for the generation of diverse products through the meticulous modulation of organocopper intermediate formation using ligands, bases, solvents, and other reaction parameters.

In the investigation of these transformations, despite emphasizing the successful implementation of various catalytic modes, we have identified several unresolved challenges and ambiguous mechanisms in this field. For instance, the reaction mechanism of copper-catalyzed aryl halides remains unclear (whether it involves two-electron oxidative addition and what factors enable this process). Additionally, the addition of the active Cu–[Si] species to alkenes or alkynes and their isomerization to carbene in carbonylation reactions have not been realized. Although 1,4-copper migration and 1,3-copper migration have been achieved,^112–114 their application in carbonylation reactions remains unaccomplished. Furthermore, while palladium-catalyzed chain walking has matured,^115–119 copper-catalyzed remote carbonylation has not been realized. To address these challenges, innovative strategies are required, such as designing novel silicon-containing reagents or adopting synergistic catalysis combining photoredox and copper systems. Our research group is actively exploring these challenging reactions and investigating their mechanisms, with the aim of further expanding the potential of copper-catalyzed carbonylation reactions and contributing to the development of green, sustainable, and efficient catalytic systems.

Conflicts of interest

There are no conflicts to declare.

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.

Acknowledgements

We appreciate the financial support provided by the National Key R&D Program of China (2023YFA1507500) and DICP.

References

1. Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, 2000.
2. Transition Metal Catalyzed Carbonylation Reactions: Carbonylative Activation of C−X Bonds, ed. M. Beller and X.-F. Wu, Springer, 2013.
3. L.-C. Wang and X.-F. Wu, Single-electron-transfer-mediated carbonylation reactions, Acc. Chem. Res., 2025, 58, 1036–1050.
4. 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.
5. (a) X.-F. Wu, H. Neumann and M. Beller, Synthesis of heterocycles via palladium-catalyzed carbonylations, Chem. Rev., 2013, 113, 1–35; (b) K. Ma, B. S. Martin, X. Yin and M. Dai, Natural product syntheses via carbonylative cyclizations, Nat. Prod. Rep., 2019, 36, 174–219; (c) L.-J. Cheng and N. P. Mankad, C–C and C–X coupling reactions of unactivated alkyl electrophiles using copper catalysis, Chem. Soc. Rev., 2020, 49, 8036–8064; (d) S. Zhao and N. P. Mankad, Metal-catalysed radical carbonylation reactions, Catal. Sci. Technol., 2019, 9, 3603–3616; (e) Y. Yuan and X.-F. Wu, Generation and transformation of α-oxy carbene intermediates enabled by copper-catalyzed carbonylation, Green Carbon, 2024, 2, 70–80.
6. J.-B. Peng, H.-Q. Geng and X.-F. Wu, The chemistry of CO: Carbonylation, Chem, 2019, 5, 526–552.
7. T. W. Dekleva and D. Forster, The Rhodium-catalyzed carbonylation of linear primary alcohols, J. Am. Chem. Soc., 1985, 107, 3565–3567.
8. A. Haynes, P. M. Maitlis, G. E. Morris, G. J. Sunley, H. Adams, P. W. Badger, C. M. Bowers, D. B. Cook, P. I. P. Elliott, T. Ghaffar, H. Green, T. R. Griffin, M. Payne, J. M. Pearson, M. J. Taylor, P. W. Vickers and R. J. Watt, Promotion of Iridium-catalyzed methanol carbonylation: mechanistic studies of the cativa process, J. Am. Chem. Soc., 2004, 126, 2847–2861.
9. J.-B. Peng, F.-P. Wu and X.-F. Wu, First-row transition-metal-catalyzed carbonylative transformations of carbon electrophiles, Chem. Rev., 2019, 119, 2090–2127.
10. W. Bauer, Methacrylic acid and derivatives, Ullmann's encyclopedia of industrial chemistry, Wiley, 2011.
11. L.-C. Wang and X.-F. Wu, Copper-catalyzed photoinduced carbonylation of C1–C3 gaseous alkanes, Nat. Commun., 2025, 16, 4663.
12. X.-F. Wu, H. Neumann and M. Beller, Palladium-catalyzed carbonylative coupling reactions between Ar–X and carbon nucleophiles, Chem. Soc. Rev., 2011, 40, 4986–5009.
13. A. Schoenberg, I. Bartoletti and R. F. Heck, Palladium-catalyzed carboalkoxylation of aryl, benzyl, and vinylic halides, J. Org. Chem., 1974, 39, 3318–3326.
14. S. Sumino, A. Fusano, T. Fukuyama and I. Ryu, Carbonylation reactions of alkyl iodides through the interplay of carbon radicals and Pd catalysts, Acc. Chem. Res., 2014, 47, 1563–1574.
15. H. Li, K. Dong, H. Jiao, H. Neumann, R. Jackstell and M. Beller, The scope and mechanism of palladium-catalysed Markovnikov alkoxycarbonylation of alkenes, Nat. Chem., 2016, 8, 1159–1166.
16. X. Fang, H. Li, R. Jackstell and M. Beller, Palladium-catalyzed alkoxycarbonylation of conjugated dienes under acid-free conditions: atom-economic synthesis of β,γ-unsaturated esters, Angew. Chem., Int. Ed., 2014, 53, 9030–9034.
17. H. Li, K. Dong, H. Neumann and M. Beller, Palladium-catalyzed hydroamidocarbonylation of olefins to imides, Angew. Chem., Int. Ed., 2015, 54, 10239–10243.
18. J. Liu, H. Li, R. Dühren, J. Liu, A. Spannenberg, R. Franke, R. Jackstell and M. Beller, Markovnikov-selective palladium catalyst for carbonylation of alkynes with heteroarenes, Angew. Chem., Int. Ed., 2017, 56, 11976–11980.
19. J. Liu, J. Yang, W. Baumann, R. Jackstell and M. Beller, Stereoselective Synthesis of highly substituted conjugated dienes via Pd-catalyzed carbonylation of 1,3-diynes, Angew. Chem., Int. Ed., 2019, 58, 10683–10687.
20. J. Liu, J. Yang, C. Schneider, R. Franke, R. Jackstell and M. Beller, Tailored palladium catalysts for selective synthesis of conjugated enynes by monocarbonylation of 1,3-diynes, Angew. Chem., Int. Ed., 2020, 59, 9032–9040.
21. Y. Ge, F. Ye, J. Liu, J. Yang, A. Spannenberg, H. Jiao, R. Jackstell and M. Beller, Ligand-controlled palladium-catalyzed carbonylation of alkynols: Highly selective synthesis of α-methylene-β-lactones, Angew. Chem., Int. Ed., 2020, 59, 21585–21590.
22. J. Yang, J. Liu, Y. Ge, W. Huang, H. Neumann, R. Jackstell and M. Beller, Direct and selective synthesis of adipic and other dicarboxylic acids by palladium-catalyzed carbonylation of allylic alcohols, Angew. Chem., Int. Ed., 2020, 59, 20394–20398.
23. J. Yang, J. Liu, Y. Ge, W. Huang, F. Ferretti, H. Neumann, H. Jiao, R. Franke, R. Jackstell and M. Beller, Efficient palladium-catalyzed carbonylation of 1,3-dienes: Selective synthesis of adipates and other aliphatic diesters, Angew. Chem., Int. Ed., 2021, 60, 9527–9533.
24. Z. Cao, Q. Wang, H. Neumann and M. Beller, Regiodivergent carbonylation of alkenes: Selective palladium-catalyzed synthesis of linear and branched selenoesters, Angew. Chem., Int. Ed., 2024, 63, e202313714.
25. Y. Ge, W. Huang, S. Ahrens, A. Spannenberg, R. Jackstell and M. Beller, Synthesis of non-equivalent diamides and amido-esters via Pd-catalysed carbonylation, Nat. Synth., 2024, 3, 202–213.
26. J. Yang, J. Liu, H. Neumann, R. Franke, R. Jackstell and M. Beller, Direct synthesis of adipic acid esters via palladium-catalyzed carbonylation of 1,3-dienes, Science, 2019, 366, 1514–1517.
27. L.-J. Cheng and N. P. Mankad, Copper-catalyzed carbonylative coupling of alkyl halides, Acc. Chem. Res., 2021, 54, 2261–2274.
28. F. Zhao, H.-J. Ai and X.-F. Wu, Copper-catalyzed substrate-controlled carbonylative synthesis of α-keto amides and amides from alkyl halides, Angew. Chem., Int. Ed., 2022, 61, e202200062.
29. Acetic Anhydride Market Size, Share, Price Trends & Forecast 2021–2026. https://www.imarcgroup.com/acetic-anhydride-marketreport (accessed 2022-11-30).
30. A. H. Tullo, Making-Wood-Last-Forever-Acetylation, Chem. Eng. News. https://cen.acs.org/articles/90/i32/Making-Wood-Last-Forever-Acetylation.html (accessed 2022-11-30).
31. J. A. I. Olmsted, Synthesis of Aspirin: A general chemistry experiment, J. Chem. Educ., 1998, 75, 1261.
32. P. Tung and N. P. Mankad, Light-mediated synthesis of aliphatic anhydrides by Cu-catalyzed carbonylation of alkyl halides, J. Am. Chem. Soc., 2023, 145, 9423–9427.
33. P. Tung and N. P. Mankad, Photochemical synthesis of acyl fluorides using copper-catalyzed fluorocarbonylation of alkyl iodides, Org. Lett., 2024, 26, 3299–3303.
34. P. Yang, Y.-H. Zhao and X.-F. Wu, Photoinduced copper-catalyzed alkoxycarbonylation of alkyl fluorides, Org. Chem. Front., 2024, 11, 2462–2467.
35. H.-Q. Geng and X.-F. Wu, Copper-catalyzed alkoxycarbonylation of alkyl iodides for the synthesis of aliphatic esters: Hydrogen makes the difference, Org. Lett., 2021, 23, 8062–8066.
36. Y. Chen, L. Su and H. Gong, Copper-catalyzed and indium-mediated methoxycarbonylation of unactivated alkyl iodides with balloon CO, Org. Lett., 2019, 21, 4689–4693.
37. O. Adaoudi, J. Le Bescont, A. Bruneau-Voisine and G. Evano, Copper-catalyzed carbonylative cross-coupling of alkyl iodides with alcohols and sodium hydroxide: Synthesis of esters and carboxylic acids, Synthesis, 2023, 668–676.
38. Z. Yin, Z. Wang and X.-F. Wu, Carbonylative coupling of N-chloroamines with alcohols: Synthesis of esterification reagents, Org. Bio. Chem., 2018, 16, 2643–2646.
39. S. Zhao and N. P. Mankad, Synergistic copper-catalyzed reductive aminocarbonylation of alkyl iodides with nitroarenes, Org. Lett., 2019, 21, 10106–10110.
40. Z. Yin, Z. Wang, W. Li and X.-F. Wu, Copper-catalyzed carbonylative cross-coupling of arylboronic acids with N-chloroamines for the synthesis of aryl amides, Eur. J. Org. Chem., 2017, 1769–1772.
41. F. Zhao, P. Russo, R. Mancuso, B. Gabriele and X.-F. Wu, Copper-catalyzed carbonylative coupling of alkyl iodides with phenols for the synthesis of esters, J. Catal., 2022, 413, 907–912.
42. J. Ling, A. Bruneau-Voisine, G. Journot and G. Evano, Copper-catalyzed carbonylative cross-coupling of alkyl iodides and amines, Chem. – Eur. J., 2022, 28, e202201356.
43. Y. Zhang, Z.-P. Bao, C.-S. Kuai and X.-F. Wu, Copper-catalyzed visible-light-induced ring-opening carbonylation of sulfonium salts, J. Catal., 2023, 426, 1–5.
44. L.-J. Cheng and N. P. Mankad, Cu-catalyzed carbonylative silylation of alkyl halides: Efficient access to acylsilanes, J. Am. Chem. Soc., 2020, 142, 80–84.
45. L.-J. Cheng, S. Zhao and N. P. Mankad, One-step synthesis of acylboron compounds via copper-catalyzed carbonylative borylation of alkyl halides, Angew. Chem., Int. Ed., 2021, 60, 2094–2098.
46. S. Zhao and N. P. Mankad, Cu-catalyzed hydroxymethylation of unactivated alkyl iodides with CO to provide one-carbon-extended alcohols, Angew. Chem., Int. Ed., 2018, 57, 5867–5870.
47. F.-P. Wu and X.-F. Wu, Copper-catalyzed borylative methylation of alkyl iodides with CO as the C1 source: Advantaged by faster reaction of CuH over CuBpin, Angew. Chem., Int. Ed., 2021, 60, 11730–11734.
48. L.-J. Cheng and N. P. Mankad, Cu-catalyzed hydrocarbonylative C–C coupling of terminal alkynes with alkyl iodides, J. Am. Chem. Soc., 2017, 139, 10200–10203.
49. L.-J. Cheng, S. M. Islam and N. P. Mankad, Synthesis of allylic alcohols via Cu-catalyzed hydrocarbonylative coupling of alkynes with alkyl halides, J. Am. Chem. Soc., 2018, 140, 1159–1164.
50. L.-J. Cheng and N. P. Mankad, Copper-catalyzed borocarbonylative coupling of internal alkynes with unactivated alkyl halides: Modular synthesis of tetrasubstituted β-borylenones, Angew. Chem., Int. Ed., 2018, 57, 10328–10332.
51. F.-P. Wu, Y. Yuan, C. Schünemann, P. C. J. Kamer and X.-F. Wu, Copper-catalyzed regioselective borocarbonylative coupling of unactivated alkenes with alkyl halides: Synthesis of β-boryl ketones, Angew. Chem., Int. Ed., 2020, 59, 10451–10455.
52. J.-B. Peng and X.-F. Wu, Ligand- and solvent-controlled regio- and chemodivergent carbonylative reactions, Angew. Chem., Int. Ed., 2018, 57, 1152–1160.
53. H.-J. Ai, W. Lu and X.-F. Wu, Ligand-controlled regiodivergent thiocarbonylation of alkynes toward linear and branched α,β-unsaturated thioesters, Angew. Chem., Int. Ed., 2021, 60, 17178–17184.
54. T. Xu and H. Alper, Pd-catalyzed chemoselective carbonylation of aminophenols with iodoarenes: alkoxycarbonylation vs aminocarbonylation, J. Am. Chem. Soc., 2014, 136, 16970–16973.
55. Z.-P. Bao and X.-F. Wu, Palladium-catalyzed direct carbonylation of bromoacetonitrile to synthesize 2-cyano-N-acetamide and 2-cyanoacetate compounds, Angew. Chem., Int. Ed., 2023, 62, e202301671.
56. S. Manna, Q. Dherbassy, G. J. P. Perry and D. J. Procter, Enantio- and diastereoselective synthesis of homopropargyl amines by copper-catalyzed coupling of imines, 1,3-enynes, and diborons, Angew. Chem., Int. Ed., 2020, 59, 4879–4882.
57. Z. Li, L. Zhang, M. Nishiura and Z. Hou, Copper-catalyzed umpolung of imines through carbon-to-nitrogen boryl migration, ACS Catal., 2019, 9, 4388–4393.
58. F.-P. Wu and X.-F. Wu, Ligand-controlled copper-catalyzed regiodivergent carbonylative synthesis of α-amino ketones and α-boryl amides from imines and alkyl iodides, Angew. Chem., Int. Ed., 2021, 60, 695–700.
59. C. M. R. Volla, I. Atodiresei and M. Rueping, Catalytic C–C bond-forming multi-component cascade or domino reactions: Pushing the boundaries of complexity in asymmetric organocatalysis, Chem. Rev., 2014, 114, 2390–2431.
60. F.-P. Wu, Y. Yuan and X.-F. Wu, Copper-catalyzed 1,2-trifluoromethylation carbonylation of unactivated alkenes: Efficient access to β-trifluoromethylated aliphatic carboxylic acid derivatives, Angew. Chem., Int. Ed., 2021, 60, 25787–25792.
61. Y. Zhang, Y. Yuan, H.-Q. Geng, J.-X. Xu and X.-F. Wu, Visible light-induced perfluoroalkylative carbonylation of unactivated alkenes, J. Catal., 2022, 413, 214–220.
62. S.-S. Yan, R. Jackstell and M. Beller, Copper-catalyzed selective amino-alkoxycarbonylation of unactivated alkenes with CO, J. Am. Chem. Soc., 2025, 147, 6464–6471.
63. Y. Zhang, B.-H. Teng and X.-F. Wu, Copper-catalyzed trichloromethylative carbonylation of ethylene, Chem. Sci., 2024, 15, 1418–1423.
64. Y. Zhang, H.-J. Ai and X.-F. Wu, Copper-catalyzed carbonylative synthesis of pyrrolidine-containing amides from γ,δ-unsaturated aromatic oxime esters, Org. Chem. Front., 2020, 7, 2986–2990.
65. Y. Zhang, Z. Yin and X.-F. Wu, Copper-catalyzed carbonylative synthesis of β-homoprolines from N-fluoro-sulfonamides, Org. Lett., 2020, 22, 1889–1893.
66. F. Zhao, X.-W. Gu, R. Franke and X.-F. Wu, Copper-catalyzed 1,2-dicarbonylative cyclization of alkenes with alkyl bromides via radical cascade process, Angew. Chem., Int. Ed., 2022, 61, e202214812.
67. N. Zhu, H. Yao, X. Zhang and H. Bao, Metal-catalyzed asymmetric reactions enabled by organic peroxides, Chem. Soc. Rev., 2024, 53, 2326–2349.
68. K. Chen, Q. Zeng, L. Xie, Z. Xue, J. Wang and Y. Xu, Functional-group translocation of cyano groups by reversible C–H sampling, Nature, 2023, 620, 1007–1012.
69. T. J. Fazekas, J. W. Alty, E. K. Neidhart, A. S. Miller, F. A. Leibfarth and E. J. Alexanian, Diversification of aliphatic C–H bonds in small molecules and polyolefins through radical chain transfer, Science, 2022, 375, 545–550.
70. L.-C. Wang, B. Chen and X.-F. Wu, Cobalt-catalyzed direct aminocarbonylation of ethers: Efficient access to α-amide substituted ether derivatives, Angew. Chem., Int. Ed., 2022, 61, e202203797.
71. L.-C. Wang, B. Chen, Y. Zhang and X.-F. Wu, Nickel-catalyzed four-component carbonylation of ethers and olefins: Direct access to γ-oxy esters and amides, Angew. Chem., Int. Ed., 2022, 61, e202207970.
72. L.-C. Wang, Y. Yuan, Y. Zhang and X.-F. Wu, Cobalt-catalyzed aminoalkylative carbonylation of alkenes toward direct synthesis of γ-amino acid derivatives and peptides, Nat. Commun., 2023, 14, 7439.
73. Z. Yin, Y. Zhang, S. Zhang and X.-F. Wu, Copper-catalyzed intra- and intermolecular carbonylative transformation of remote C(sp³)H bonds in N-fluoro-sulfonamides, J. Catal., 2019, 377, 507–510.
74. Y. Li, K. Dong, F. Zhu, Z. Wang and X.-F. Wu, Copper-catalyzed carbonylative coupling of cycloalkanes and amides, Angew. Chem., Int. Ed., 2016, 55, 7227–7230.
75. Y. Li, C. Wang, F. Zhu, Z. Wang, P. H. Dixneuf and X.-F. Wu, Copper-catalyzed alkoxycarbonylation of alkanes with alcohols, ChemSusChem, 2017, 10, 1341–1345.
76. L. Lu, F. Qiu, H. Alhumade, H. Zhang and A. Lei, Tuning the oxidative mono- or double-carbonylation of alkanes with CO by choosing a Co or Cu Catalyst, ACS Catal., 2022, 12, 9664–9669.
77. Y. Li, C. Wang, F. Zhu, Z. Wang, J. F. Soulé, P. H. Dixneuf and X.-F. Wu, An unexpected copper-catalyzed carbonylative acetylation of amines, Chem. Commun., 2017, 53, 142–144.
78. Y. Li, F. Zhu, Z. Wang and X.-F. Wu, A copper-catalyzed carbonylative four-component reaction of ethene and aliphatic olefins, Chem. Commun., 2018, 54, 1984–1987.
79. H.-Q. Geng, T. Meyer, R. Franke and X.-F. Wu, Copper-catalyzed hydroformylation and hydroxymethylation of styrenes, Chem. Sci., 2021, 12, 14937–14943.
80. F.-P. Wu, X. Luo, U. Radius, T. B. Marder and X.-F. Wu, Copper-catalyzed synthesis of stereodefined cyclopropyl bis(boronates) from alkenes with CO as the C1 Source, J. Am. Chem. Soc., 2020, 142, 14074–14079.
81. F.-P. Wu, Y. Yang, D. P. Fuentes and X.-F. Wu, Copper-catalyzed carbonylative catenation of olefins: Direct synthesis of γ-boryl esters, Chem, 2022, 8, 1982–1992.
82. H.-Q. Geng, Y.-H. Zhao, P. Yang and X.-F. Wu, Copper-catalyzed carbonylative multi-component borylamidation of alkenes for synthesizing γ-boryl amides with CO as both methylene and carbonyl sources, Chem. Sci., 2024, 15, 3996–4004.
83. Y. Yuan, F.-P. Wu and X.-F. Wu, Copper-catalyzed borofunctionalization of styrenes with B₂pin₂ and CO, Chem. Sci., 2021, 12, 13777–13781.
84. Y. Yuan, Y. Zhang, J.-X. Xu and X.-F. Wu, Copper-catalyzed ligand-controlled selective borocarbonylation of α-substituted styrenes toward β-boryl aldehydes and cyclopropyl boronate esters, CCS Chem., 2022, 5, 1866–1875.
85. H.-Q. Geng and X.-F. Wu, Copper-catalyzed synthesis of β-boryl cyclopropanes via 1,2-borocyclopropanation of aryl olefins with CO as the C1 source, Chem. Sci., 2023, 14, 5638–5642.
86. F.-P. Wu, H.-Q. Geng and X.-F. Wu, Copper-catalyzed boroaminomethylation of olefins to γ-boryl amines with CO as C1 Source, Angew. Chem., Int. Ed., 2022, 61, e202211455.
87. J.-B. Peng, X.-L. Liu, L. Li and X.-F. Wu, Palladium-catalyzed enantioselective carbonylation reactions, Sci. China: Chem., 2022, 65, 441–461.
88. J. Li, W. Chang, W. Ren, J. Dai and Y. Shi, Palladium-catalyzed highly regio- and enantioselective hydroesterification of aryl olefins with phenyl formate, Org. Lett., 2016, 18, 5456–5459.
89. X. Wang, B. Wang, X. Yin, W. Yu, Y. Liao, J. Ye, M. Wang, L. Hu and J. Liao, Palladium-catalyzed enantioselective thiocarbonylation of styrenes, Angew. Chem., Int. Ed., 2019, 58, 12264–12270.
90. Y. Yuan, F.-P. Wu, C. Schünemann, J. Holz, P. C. J. Kamer and X.-F. Wu, Copper-catalyzed carbonylative hydroamidation of styrenes to branched Amides, Angew. Chem., Int. Ed., 2020, 59, 22441–22445.
91. Y. Yuan, Y. Zhang, W. Li, Y. Zhao and X.-F. Wu, Regioselective and Enantioselective Copper-catalyzed hydroaminocarbonylation of unactivated alkenes and alkynes, Angew. Chem., Int. Ed., 2023, 62, e202309993.
92. Y. Yuan, Y. Zhang and X.-F. Wu, Enantioselective synthesis of γ-chiral amides via copper-catalyzed reductive relay hydroaminocarbonylation, Nat. Commun., 2024, 15, 6705.
93. Y. Yuan, S. Shao, M. Hu, J. Zhu, Y. Zhao and X.-F. Wu, Copper-catalyzed asymmetric hydroaminocarbonylation of unactivated internal alkenes, CCS Chem., 2024, 7, 965–972.
94. S. Shao, Y. Yuan, A. Schmoll and X.-F. Wu, Copper-catalyzed asymmetric carbonylative hydroallylation of vinylarenes, Chem. Sci., 2025, 16, 10951–10956.
95. F.-P. Wu, J. Holz, Y. Yuan and X.-F. Wu, Copper-catalyzed carbonylative synthesis of β-boryl amides via boroamidation of alkenes, CCS Chem., 2020, 3, 2643–2654.
96. C.-C. Li, Á. Adorján, M. Sofiadis, T. Schulte, J. Mateos, M. Rippegarten and T. Ritter, Nitrate reduction for deaminative Suzuki–Miyaura coupling of anilines, Angew. Chem., Int. Ed., 2025, 64, e202504012.
97. J. E. A. Russell, E. D. Entz, I. M. Joyce and S. R. Neufeldt, Nickel-catalyzed Stille cross coupling of C–O electrophiles, ACS Catal., 2019, 9, 3304–3310.
98. J. A. Killion, W. T. Darrow, M. R. Brennan, C. A. Leahy and A. R. Fout, Cobalt-catalyzed Kumada coupling forming sterically encumbered C–C bonds, Organometallics, 2022, 41, 1769–1776.
99. S.-K. Kang, T. Yamaguchi, T.-H. Kim and P.-S. Ho, Copper-catalyzed cross-coupling and carbonylative cross-coupling of organostannanes and organoboranes with hypervalent iodine compounds, J. Org. Chem., 1996, 61, 9082–9083.
100. L. Cheng, Y. Zhong, Z. Ni, H. Du, F. Jin, Q. Rong and W. Han, Copper-catalyzed carbonylative Suzuki coupling of aryliodides with arylboronic acids under ambient pressure of carbon monoxide, RSC Adv., 2014, 4, 44312–44316.
101. D. R. Pye, L.-J. Cheng and N. P. Mankad, Cu/Mn bimetallic catalysis enables carbonylative Suzuki–Miyaura coupling with unactivated alkyl electrophiles, Chem. Sci., 2017, 8, 4750–4755.
102. J. Zhang and X.-F. Wu, Copper-catalyzed carbonylative Suzuki–Miyaura coupling of un-activated alkyl bromides with aryl boronates, Chin. J. Catal., 2025, 73, 146–152.
103. H. Sheng, Z. Chen and Q. Song, Palladium-catalyzed difluorocarbene transfer enabled divergent synthesis of γ-butenolides and ynones from iodobenzene and terminal alkynes, J. Am. Chem. Soc., 2024, 146, 1722–1731.
104. Y. Yuan, F.-P. Wu, A. Spannenberg and X.-F. Wu, Cu/Pd-catalyzed borocarbonylative trifunctionalization of alkynes and allenes: Synthesis of β-geminal-diboryl ketones, Sci. China: Chem., 2021, 64, 2142–2153.
105. Y. Yuan, F.-P. Wu, J.-X. Xu and X.-F. Wu, Four-component borocarbonylation of vinylarenes enabled by cooperative Cu/Pd Catalysis: Access to β-boryl ketones and β-boryl vinyl esters, Angew. Chem., Int. Ed., 2020, 59, 17055–17061.
106. F.-P. Wu and X.-F. Wu, Catalyst-controlled selective borocarbonylation of benzylidenecyclopropanes: regiodivergent synthesis of γ-vinylboryl ketones and β-cyclopropylboryl ketones, Chem. Sci., 2022, 13, 4321–4326.
107. Y. Yuan, J.-X. Xu and X.-F. Wu, Cooperative Cu/Pd-catalyzed borocarbonylation of ethylene, Chem. Commun., 2022, 58, 12110–12113.
108. Y. Li and X.-F. Wu, Copper/iron co-catalyzed alkoxycarbonylation of unactivated alkyl bromides, Comm. Chemun., 2018, 1, 39.
109. J. Liu, R. Zhang, S. Wang, W. Sun and C. Xia, A general and efficient copper catalyst for the double carbonylation reaction, Org. Lett., 2009, 11, 1321–1324.
110. H. Yang, Z.-P. Bao, L.-C. Wang and X.-F. Wu, Copper-catalyzed direct carbonylation of carbenes toward the synthesis of propanedioic acid derivatives, Org. Lett., 2023, 25, 1963–1968.
111. Z. Wang, Z. Yin and X.-F. Wu, Copper-catalyzed carbonylative transformations of indoles with hexaketocyclohexane, Chem. Commun., 2018, 54, 4798–4801.
112. H. Moniwa, M. Yamanaka and R. Shintani, Copper-catalyzed regio- and stereoselective formal hydro(borylmethylsilyl)ation of internal alkynes via alkenyl-to-alkyl 1,4-copper migration, J. Am. Chem. Soc., 2023, 145, 23470–23477.
113. P. Dominguez-Molano, R. Weeks, R. J. Maza, J. J. Carbó and E. Fernández, Boron-copper 1,3-rearrangement: the new concept behind the boryl migration from C(sp²) in alkenyl boranes to C(sp³), Angew. Chem., Int. Ed., 2023, 62, e202304791.
114. P. Dominguez-Molano, A. Solé-Daura, J. J. Carbó and E. Fernández, Remote 1,4-carbon-to-carbon boryl migration: From a mechanistic challenge to a valuable synthetic application of bicycles, Adv. Sci., 2024, 11, 2309779.
115. Z. Wang, C. Shen and K. Dong, Palladium-catalyzed enantioselective migratory hydroamidocarbonylation of amide-linked alkenes to access chiral α-alkyl succinimides, Angew. Chem., Int. Ed., 2024, 63, e202410967.
116. X.-J. Zou, Z.-X. Jin, H.-Y. Yang, F. Wu, Z.-H. Ren and Z.-H. Guan, Palladium-catalyzed inward isomerization hydroaminocarbonylation of alkenes, Angew. Chem., Int. Ed., 2024, 63, e202406226.
117. J. Li, T. Shen, Y. Zhuang, Y. Fu and Y. Shi, Pd-catalyzed highly regioselective migratory hydroesterification of internal olefins with formates, Chin. Chem. Lett., 2025, 36, 110599.
118. K. Dong, R. Sang, J. Liu, R. Razzaq, R. Franke, R. Jackstell and M. Beller, Palladium-catalyzed carbonylation of sec- and tert-alcohols, Angew. Chem., Int. Ed., 2017, 56, 6203–6207.
119. J. Liu, J. Yang, F. Ferretti, R. Jackstell and M. Beller, Pd-catalyzed selective carbonylation of gem-difluoroalkenes: A practical synthesis of difluoromethylated esters, Angew. Chem., Int. Ed., 2019, 58, 4690–4694.

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