Transition-Metal-Catalyzed (Ni, Pd) Remote Difunctionalization of Alkenes via Chain-Walking Strategies

Abstract

Alkenes are not only crucial feedstocks in the chemical industry but are also extensively present in natural products, pharmaceuticals, and organic functional materials. The direct difunctionalization of alkenes has emerged as a powerful and valuable strategy for the construction of highly functionalized organic skeletons. This short review highlights recent advancements in transition-metal-catalyzed remote 1,n-difunctionalization (n > 2) reactions of alkenes with the focus on innovative strategies involving chain-walking processes to construct complex, highly functionalized organic frameworks.

1 Introduction

2 Nickel Catalysis

3 Palladium Catalysis

4 Conclusion

Introduction

Alkenes, as readily available, reactive, and cost-effective feedstocks, play an indispensable role in the modern chemical industry and everyday life.[1] Furthermore, alkenes are widely found in various natural products, pharmaceuticals, and organic functional materials.[2] In recent decades, the direct difunctionalization of alkenes has emerged as a powerful and valuable strategy for constructing highly functionalized skeletons in organic synthesis.[3] This approach allows for the simultaneous introduction of two new functional groups across a double bond in a single step with remarkable efficiency. Therefore, in recent years, the development of novel methodologies for achieving this transformation has consistently garnered significant attention from synthetic chemists.

Within this research field, numerous studies have been focused on adjacent difunctionalization reactions, including 1,1- and 1,2-difunctionalization.[4] [5] Despite its potential, the remote 1,n-difunctionalization (n > 2) of alkenes involving metal migration remains underexplored, with only a limited number of reports available.[6] This emerging and highly promising strategy not only allows for the selective introduction of functional groups at double bond but also enables remote C–H functionalization through an innovative chain-walking processes (Figure [1]). To date, only a few review articles have partially addressed this approach. In 2020, both the Yin group and the Giri group highlighted significant progress in transition-metal-catalyzed 1,n-difunctionalization (n ≠ 2) of alkenes involving metal migration.[6a] [b] Subsequently, the Wei group provided an overview of the 1,3-difunctionalization of alkenes, covering both metal and radical migration mechanisms.[6c] However, these reviews primarily summarized developments up to 2019. In 2021, the Chatterjee group provided a comprehensive overview of chain-walking reactions in transition-metal-catalyzed remote C–H functionalization.[6d] In 2023 and 2024, the Martin group published two reviews focused specifically on Ni-catalyzed remote C(sp³)–H functionalization via chain-walking strategies.[6e] [f]

In this short review, we aim to provide a concise yet comprehensive overview of the latest advancements in transition-metal-catalyzed remote 1,n-difunctionalization (n > 2) of alkenes in constructing complex molecular architectures via chain-walking strategies. We categorize the studies based on transition metal systems, specifically nickel and palladium catalysis. Furthermore, we provide an in-depth discussion of proposed reaction mechanisms.

Nickel Catalysis

Nickel catalysts have attracted considerable attention in organic synthesis owing to their low cost, broad applicability, and high reaction efficiency.[7] Additionally, the multiple oxidation states of nickel facilitate a wide range of redox pathways in diverse catalytic processes.[8]

In 2018, the Giri group developed a Ni-catalyzed 1,3-diarylation reaction of unactivated alkenes via a chain-walking strategy (Scheme [1a]).[9] In this reaction, (PhO)₃P was found to be an excellent ligand to promote this process, providing a variety of β,δ-diaryl ketones with good yields. Both aryl iodides and arylzinc reagents were employed as arylation sources in their study. Notably, aryl iodides undergo arylation at the δ-position, whereas arylzinc reagents react at the β-position. While the imine group was used as a crucial directing group to achieve the chain-walking process, it could be easily converted into the carbonyl group after simple H⁺ workup procedures. Control experiments indicate that the (PhO)₃P ligand facilitates the contraction of an unstable six-membered nickelacycle intermediate to a stable five-membered nickelacycle intermediate.

Based on these findings, a proposed mechanism is provided in Scheme [1b]. Initially, the coordination of alkene substrate 1, NiBr₂, and (PhO)₃P generates intermediate 1A, which undergoes oxidative addition to aryl iodide 2 to yield intermediate 1B. Subsequently, the intramolecular alkene insertion provides the nickelacycle intermediate 1C, which further coordinates with (PhO)₃P to form the nickelacycle intermediate 1D. Next, β-hydride elimination of 1D produces intermediate 1E, which is transformed into a more stable five-membered nickelacycle intermediate 1F via migratory insertion of the double bond into the Ni–H bond, thereby achieving the Ni-mediated chain-walking process. Next, the transmetalation step between arylzinc reagent 3 and 1F provides intermediate 1G. Finally, reductive elimination of 1G produces intermediate 1H, which is converted into the desired product 4 after simple H⁺ workup procedures.

In 2019, the Yin group reported a Ni-catalyzed remote arylboration of allylbenzenes with aryl bromides and bis(pinacolato)diboron (B₂pin₂) (Scheme [2a]).[10] This protocol enabled the synthesis of diarylalkylboronic esters in moderate to good yields. PyrOx-type ligand L1 played a crucial role in this migratory reaction, yielding migratory products with excellent regioselectivity (rr). Moreover, this process not only delivers a diverse range of 1,3-arylboration products but also produces 1,4- and 1,5-arylboration products when the corresponding alkenes are utilized. The boron group enabled further transformations into a broad spectrum of valuable functional groups. Mechanistic studies suggest that an equilibrium among three alkyl nickel intermediates is involved in this migratory reaction, and the final benzylic selectivity may be determined by η³-coordination.

A plausible reaction mechanism is presented in Scheme [2b]. The initial coordination of NiBr₂·DME with PyrOx-type ligand L1 generates nickel species 2A, which undergoes transmetalation with B₂pin₂ to form nickel species 2B. The ensuing alkene insertion of nickel species 2B with substrate 5 generates nickel intermediate 2C. Subsequently, a reversible chain-walking step provides two nickel intermediates 2D and 2E. Finally, nickel intermediate 2D reacts more readily with aryl bromide 6 to form the desired arylboration product 7. Notably, nickel intermediate 2E produces the 1,1-arylboration byproduct.

In subsequent studies, the Yin group extended this Ni-catalyzed chain-walking strategy to benzyl chlorides in combination with allylarenes and B₂pin₂ (Scheme [3a]).[11] In this reaction, the 1,3-regioselective benzylboration of allylbenzenes was controlled by the choice of solvent. Specifically, 1,4-dioxane selectively produced 1,3-benzylboration products 9 in moderate yields. Furthermore, the addition of PC(Co) (cobalt tetrakis(methoxyphenyl)porphyrin) improved both the yields and the 1,3-regioselectivities. In 2023, the Yin group developed a ligand-modulated Ni-catalyzed regiodivergent alkenylboration reaction of allylarenes via a chain-walking strategy. When the diphenylethane-1,2-trans-diamine ligand L2 was employed, remote alkenylboration products 11 were obtained in moderate to good yields (Scheme [3b]).[12]

In addition to allylbenzenes, heterocyclic alkenes, including 2,5-dihydrofuran, 3,6-dihydro-2H-pyran, N-substituted 2,5-dihydro-1H-pyrroles, and 1,2,3,6-tetrahydropyridines, were also suitable substrates for the synthesis of cis-2,4-substituted saturated heterocycles via nickel-catalyzed chain-walking alkylboration reaction (Scheme [4a]). Investigations of reaction conditions indicated that the diamine-based ligand L3 was the most suitable for this transformation. Notably, 2,3-unsaturated heterocycles failed to provide the desired migratory products.[13]

A radical chain catalytic cycle is proposed in Scheme [4b]. Initially, the diamine-based ligand L3 coordinates with NiCl₂·DME to form nickel species 3A, which subsequently undergoes transmetalation to generate nickel complex 3B. Next, the alkene insertion involving nickel complex 3B gives nickel intermediate 3C. Then, β-hydride elimination of this intermediate occurs, followed by migratory insertion, to afford nickel intermediate 3E, which reacts with an alkyl radical to produce nickel intermediate 3F. Finally, reductive elimination of 3F provides the desired cis-product 14 and nickel species 3G. Furthermore, the reaction of an alkyl bromide with nickel species 3G generates an alkyl radical and regenerates nickel species 3A.

In 2023, the Yin group utilized Ni-catalyzed chain-walking alkylboration and arylboration reactions to construct cis-1,3-disubstituted cyclohexanes.[14] A range of alkyl halides and aryl bromides were reacted with cyclohexene and B₂pin₂, affording the desired products 17 in satisfactory yields (Scheme [5]).

Also in 2023, the Yin group also successfully developed a Ni-catalyzed chain-walking silylalkylation reaction of alkenes using alkyl bromides and the Suginome reagent (PhMe₂Si-Bpin), employing a diamine-based ligand L4 (Scheme [6a]).[15] This remote difunctionalization reaction demonstrated compatibility with various functional groups on the alkene substrates, including ethers, boronates, hydroxyls, and esters. Notably, both hydroxyl and ester groups could serve as remote directing groups to facilitate this chain-walking silylalkylation (Scheme [6b]). A proposed mechanism is depicted in Scheme [6c]. The initial transmetalation between a Cu(I) salt and the Suginome reagent in the presence of LiOMe produces Cu(I)-SiMe₂Ph, which subsequently undergoes a second transmetalation with the Ni(II) species 4A to form nickel intermediate 4B. Then, the alkene substrate 18 reacts with 4B to generate nickel intermediate 4C, which undergoes a chain-walking process to yield nickel intermediate 4D. Finally, the subsequent radical addition of this intermediate and reductive elimination furnish the final product 19.

In recent years, the Ni-catalyzed asymmetric organic process has earned remarkable attention owing to its potential as an efficient method for accessing chiral skeletons.[16] In 2021, the Yin group reported the Ni-catalyzed asymmetric chain-walking alkylboration of oxo-heterocyclic alkenes using chiral ligand L5 (Scheme [7a]).[13] This protocol enabled the reaction of 2,5-dihydrofuran with various primary alkyl bromides, yielding the desired chiral products 23 in moderate to good yields with excellent diastereomeric ratios (dr) and enantiomeric excesses (ee). In 2022, the Zhu group successfully achieved Ni-catalyzed asymmetric chain-walking arylboration of allylbenzenes using chiral ligand L6 and PyrOx-type ligand L1.[17] The Bpin group was subsequently transformed into a hydroxyl group upon treatment with NaBO₃·H₂O. Moreover, the desired migratory chiral alcohol derivatives 25 were isolated with high rr and excellent ee (Scheme [7b]).

In 2024, the Martin group developed a novel Ni-catalyzed remote alkylarylation of alkenes with both alkyl and aryl bromides (Scheme [8a]).[18] Unlike previous reaction models, this novel strategy involves an initial atom-transfer radical addition (ATRA) followed by a subsequent chain-walking step. Notably, this process was selectively compatible with alkyl bromides substituted with electron-withdrawing groups such as CN, ester, and C₄F₉. In addition, a proposed mechanism is provided (Scheme [8b]). Initially, the atom-transfer radical addition between alkene 26 and alkyl bromide 28 generates intermediate 5A. Concurrently, the reduction of the Ni(II) catalyst by Mn produces the Ni(0) species 5B. The subsequent oxidative addition of 5B with intermediate 5A forms intermediate 5C, which then undergoes chain-walking followed by another oxidative addition to produce intermediate 5E. Finally, reductive elimination of 5E furnishes the desired product 29 along with Ni(I) species 5F. The reduction of this Ni(I) species by Mn regenerates the Ni(0) species, thereby completing the catalytic cycle.

Palladium Catalysis

Palladium catalysis, a cornerstone of modern organic synthesis, efficiently facilitates the formation of C–C and C–heteroatom bonds through various coupling reactions, including the Suzuki–Miyaura, Heck, and Negishi reactions.[19] Furthermore, palladium catalysis has also become an indispensable tool for direct C–H bond functionalization.[20]

In the field of chain-walking reactions, pioneering work was reported by the Larock group, which introduced Pd-catalyzed remote 1,n-difunctionalization of nonconjugated dienes using aryl iodides and carbon or nitrogen nucleophiles.[21] The formation of a π-allyl Pd(II) intermediate at the distal position is more favorable compared to the π-benzyl Pd(II) intermediate, serving as the driving force for these reactions.

In 2019, the Yin group reported a pioneering Pd-catalyzed chain-walking arylboration reaction of cyclohexa-1,4-diene, achieving the synthesis of diverse cis-1,3-arylboration products in moderate to good yields (Scheme [9a]).[22] This transformation utilized aryl iodides and B₂pin₂ as coupling partners, with tetramethylammonium chloride (Me₄NCl) playing a critical role in this reaction. Specifically, Me₄NCl facilitates the formation of an active anionic palladium complex and stabilizes the Pd(0) catalyst against precipitation which is essential for the success of the reaction. Notably, prior Ni-catalyzed migration strategies had failed to deliver the desired cis-1,3-arylboration products, underscoring the unique efficiency of the Pd-catalyzed system.

Building on this work, the Yin group expanded the Pd-catalyzed chain-walking strategy in 2021 to achieve the 1,3-diarylation of cyclohexa-1,4-diene using aryl iodides and arylboronic acids as coupling partners (Scheme [9b]).[23] A particularly successful example involved the combination of phenylboronic acid and 1-iodo-4-methoxybenzene, which afforded the desired cis-1,3-diarylation product 33a in an impressive yield (81%). However, other combinations of aryl iodides and arylboronic acids proved less effective, often resulting in lower yields or failure to produce the desired products 33. This limitation was attributed to the formation of numerous Suzuki coupling byproducts, which competed with the desired diarylation pathway. Remarkably, replacing arylboronic acids with boronic acid ester significantly improved the reaction efficiency, leading to enhanced yields of the products 35 (Scheme [9c]).

The proposed mechanism for the Pd-catalyzed cis-1,3-diarylation of cyclohexa-1,4-diene is outlined in Scheme [10]. The reaction is initiated with the oxidative addition of aryl iodide 2 to the Pd(0) catalyst, generating Pd(II) species 6A. In the presence of Me₄NCl, the intermediate is converted into activated Pd(II) complex 6B, which undergoes alkene insertion followed by β-hydride elimination to form intermediate 6D. Subsequent migratory insertion produces the more stable π-allyl Pd(II) intermediate 6E. Transmetalation between boronic acid ester 34 and 6E, facilitated by NaOAc, yields intermediate 6F. Finally, reductive elimination of 6F releases the desired product 35 and regenerates the Pd(0) catalyst, completing the catalytic cycle.

In 2021, the Kochi group introduced a Pd-catalyzed remote diborylative cyclization reaction of dienes with diborons via a chain-walking strategy (Scheme [11a]).[24] The combination of 1,10-phenanthroline palladium catalyst (phen)PdMeCl and NaB(Ar^f)₄ (Ar^f = 3,5-(CF₃)₂C₆H₃) is crucial for this process. Notably, a wide range of 1,6-diene substrates bearing diverse functional groups such as esters, ketones, ethers, carboxylic acids, alcohols, and amides were compatible with this protocol. In addition to B₂pin₂, other diboron reagents afforded the desired products in moderate to good yields. A proposed catalytic cycle is shown in Scheme [11b]. Initially, (phen)PdMeCl reacts with NaB(Ar^f)₄ to form cationic methylpalladium species 7A, which transmetalates with B₂pin₂ to generate Pd(II) complex 7B. The terminal alkene of the diene substrate 36 coordinates to complex 7B, followed by an insertion process, providing intermediate 7D. Subsequently, the remaining alkene moiety of 7D undergoes insertion into the Pd–C bond, generating a five-membered intermediate 7E. This intermediate is then converted into 7F through a reversible chain-walking process. Finally, B₂pin₂ reacts with 7F to provide the desired product 37–40 and regenerate Pd(II) complex 7B.

In addition to 1,6-dienes, 1,n-dienes (n = 7, 8, 9) also served as suitable substrates for this diborylative cyclization, yielding the desired products 42 in moderate yields with excellent diastereoselectivity (Scheme [12a]). Importantly, these reactions feature two reversible chain-walking steps involving intermediates 8A to 8D (Scheme [12b]).

In 2022, the Chen group developed a Pd-catalyzed asymmetric remote 1,3-diarylation of internal enamides with arenediazonium salts and arylboronic acids (Scheme [13a]).[25] In this protocol, (S)-iPr-BiOx L8 served as the chiral ligand, while dimethyl fumarate (DMFU) and Ag₂CO₃ were employed as essential additives. With this method, a diverse range of chiral syn-1,3-diarylamine derivatives were obtained in moderate to good yields with excellent enantioselectivities. Notably, these chiral syn-1,3-diarylamine derivatives feature two non-contiguous stereogenic centers. Additionally, the proposed mechanism is illustrated in Scheme [13b]. The initial coordination of [Pd(cinnamyl)Cl]₂ with L8 forms Pd(0) species 9A, which subsequently undergoes oxidative addition with arenediazonium salt 45 to generate Pd(II) intermediate 9B. Next, the enamide substrate 43 coordinates with 9B, followed by enantioselective 1,2-migratory insertion, to yield chiral Pd(II) intermediate 9D. Subsequently, intermediate 9D is converted into benzyl palladium intermediate 9E via a chain-walking process. Finally, transmetalation between arylboronic acid 44 and 9E produces intermediate 9F, which is then transformed into the desired product 46 through reductive elimination.

In 2024, the Liu group developed Pd-catalyzed asymmetric remote aminoacetoxylation of internal alkenes using a chiral bulky (PyOx) ligand L9 (Scheme [14a]).[26] This methodology enabled the isolation of various chiral lactam derivatives in good yields with excellent enantioselectivities. Notably, PhI(OAc)₂ served as an essential oxidant, whereas other oxidants such as BQ, Cu(OAc)₂, NFSI, Selectfluor, and K₂S₂O₈ failed to produce the desired products. A plausible mechanism is illustrated in Scheme [14b]. Initially, coordination of the Pd(OAc)₂ catalyst with chiral ligand L9 generates Pd(II) species 10A. Then, this species undergoes asymmetric intramolecular trans-aminopalladation with alkene substrate 47 under acidic conditions forming Pd(II) intermediate 10B. Subsequently, the chain-walking process of 10B leads to the formation of Pd(II) intermediate 10C, which is oxidized by PhI(OAc)₂ to produce Pd(IV) intermediate 10D. Finally, reductive elimination of 10D yields the desired product 48.

In 2024, the Ge group introduced a novel Pd-catalyzed remote arylamination reaction of alkenyl alcohols using aryl iodides and amines (Scheme [15a]).[27] This reaction proceeds via a cascade of Pd-catalyzed chain-walking arylation and reductive amination steps. The presence of tetrabutylammonium trifluoromethanesulfonate (TBA·OTf) is crucial for facilitating the formation of active Pd nanoparticles (Pd NPs). A key feature of this method is the generation of aldehyde intermediates through Pd-catalyzed chain-walking arylation of alkenyl alcohols. A plausible reaction mechanism is proposed in Scheme [15b]. Initially, the Pd(II) catalyst is converted into Pd NPs in the presence of TBA·OTf. Next, the oxidative addition of Pd NPs with aryl iodide 2 generates intermediate 11A, which further reacts with alkenyl alcohol 49 to form intermediate 11B. Subsequently, chain-walking occurs on 11B to yield the intermediate 11C, which undergoes β-hydride elimination to form the crucial aldehyde intermediate 11D. Next, the reversible condensation between aldehyde intermediate 11D and amine substrate 50 provides imine intermediate 11F, which is reduced by Pd(II)–H species to yield the desired product 51.

In addition, this strategy also achieved the Pd-catalyzed remote trifunctionalization of alkenyl alcohols. The use of a 1,4-dioxane/D₂O co-solvent system enabled deuterated arylamination reactions (Scheme [16a]). Furthermore, the introduction of (HCHO)_n facilitated the formation of allylamine derivatives through methylenated arylamination reactions (Scheme [16b]).

Conclusion

In this brief review, we highlight recent advances in the remote 1,n-difunctionalization (n > 2) of alkenes, focusing on innovative chain-walking strategies enabled by nickel and palladium catalysts. These methodologies have significantly expanded the scope of alkene functionalization, allowing for selective transformations at distal carbon centers and providing access to a wide range of complex molecular structures. The first section outlines the nickel-catalyzed remote difunctionalization of alkenes, covering a range of transformations such as diarylation, arylboration, alkenylboration, alkylboration, and alkylarylation. These reactions leverage diverse chain-walking strategies to achieve selective functionalization at distal carbon centers through controlled metal migration. Specifically, the remote diarylation reaction utilizes an imine directing group in conjunction with a phosphine ligand, which facilitates the contraction of a six-membered Ni(II) intermediate into a more stable five-membered Ni(II) intermediate. Additionally, remote arylboration, alkenylboration, alkylboration, alkylarylation, and silylalkylation reactions proceed via the formation of more stable π-benzyl or π-allyl Ni(II) intermediates at the distal positions. Notably, remote silylalkylation reactions can be achieved through the formation of more stable terminal Ni(II) intermediates or by utilizing neighboring chelating groups to stabilize Ni(II) intermediates. The second part primarily focuses on the palladium-catalyzed remote difunctionalization of nonconjugated dienes. The formation of more stable Pd(II) intermediates acts as a critical driving force for these reactions. Interestingly, the Pd-catalyzed remote arylamination of alkenyl alcohols can be accomplished via a sequential Pd-catalyzed chain-walking arylation followed by reduction. Additionally, both nickel and palladium catalysis enable the remote enantioselective difunctionalization of alkenes in the presence of chiral ligands.

Despite significant advancements in this field, several challenges and opportunities for further development remain. (1) The exploration of alternative transition metal catalysts, such as Ir, Rh, Fe, Cu, and Co, for metal migration processes represents an unexplored yet promising area of research. (2) The development of enantioselective strategies to construct chiral molecular frameworks is a critical frontier that demands further investigation. (3) The integration of photochemical and electrochemical methods into the remote difunctionalization of alkenes also holds immense potential for expanding the scope and efficiency of these transformations. This short review aims to provide readers with a comprehensive understanding of recent progress in this field and to inspire the exploration of innovative strategies for remote difunctionalization of alkenes involving metal migration. By addressing these challenges and opportunities, future research can unlock new synthetic pathways and advance the field toward broader applications.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Authors

Publication History

Received: 28 February 2025

Accepted after revision: 26 March 2025

Accepted Manuscript online:
26 March 2025

Article published online:
05 May 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References

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  Search in Google Scholar
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  CrossrefSearch in Google Scholar
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  CrossrefSearch in Google Scholar
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  Search in Google Scholar
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