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Progress in Chemistry

Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Review

Organic Transformations via Controlled Aryl-to-Vinylic 1,4-Palladium Migration

  • Zhaoxia Lai 1 ,
  • Runqi Fan 1 ,
  • Xue Wang 1 ,
  • Shusheng Zhang 1 ,
  • Ting Qiu , 2, * ,
  • Chenguo Feng , 1, *
Expand
  • 1 Innovation Research Institute of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China
  • 2 Shanghai Institute of Organic Chemistry,Chinese Academy of Science,Shanghai 200032,China
* (Chenguo Feng);
(Ting Qiu)

Received date: 2025-01-09

  Revised date: 2025-02-10

  Online published: 2025-04-30

Supported by

National Natural Science Foundation of China(22271195)

Abstract

Organometallic compounds can undergo intramolecular C—H activation to form cyclometallic species,which can then undergo selective ring-opening to enable a “through space” migration of the metal atom within the molecule. Compared to the widely studied heteroatom-directed C—H activation reactions,this process is more complex and difficult to control. Over the past decade,significant progress has been made in this area,providing powerful new tools for the functionalization of remote C—H bonds. The aryl-to-vinylic 1,4-palladium migration represents one of the most significant research area in this field. Although it faces challenges,including the migration of palladium to the thermodynamically less stable vinyl position and the inherent diverse reactivity of alkenes,it provides a novel strategy for the highly stereoselective synthesis of polysubstituted alkenes. Owing to its considerable academic and practical significance,this method has garnered widespread attention.This review summarizes the key mechanisms of aryl-to-vinylic 1,4-palladium migration,various transformation reactions,and potential synthetic applications. Finally,the challenges encountered in this field and prospects for future development are discussed.

Contents

1 Introduction

2 Palladium migration followed by reaction with C(sp2)coupling reagents

2.1 Alkenyl coupling partners

2.2 Aryl coupling partners

2.3 Diazo coupling partners

2.4 Carbonylation partners

3 Palladium migration followed by reaction with C(sp3)coupling reagents

4 Palladium migration followed by reaction with C(sp)coupling reagents

5 Palladium migration followed by reaction with heteroatom coupling reagents

6 Conclusion and outlook

Cite this article

Zhaoxia Lai , Runqi Fan , Xue Wang , Shusheng Zhang , Ting Qiu , Chenguo Feng . Organic Transformations via Controlled Aryl-to-Vinylic 1,4-Palladium Migration[J]. Progress in Chemistry, 2025 , 37(5) : 639 -648 . DOI: 10.7536/PC20250103

1 Introduction

Transition metal-catalyzed activation of inert C—H bonds enables the direct conversion of widely existing C—H bonds in molecules into carbon-carbon bonds or carbon-heteroatom bonds, representing an important topic in the field of organic chemistry. Compared with traditional synthetic techniques, this approach can significantly shorten reaction steps and reduce waste emissions, thereby bringing innovative technology for the synthesis of complex molecules and green chemistry. However, to achieve regio- and stereo-selectivity in the reaction, C—H bond activation often relies on heteroatom directing groups, which typically require additional steps for installation and removal of these directing groups[12-3]. In recent years, studies have revealed that certain organotransition metal compounds undergo intramolecular C—H activation to form cyclometalated compounds, which subsequently undergo selective ring-opening to realize "through-space" migration of the metal within the molecule (Fig. 1). The migrated metal-containing compounds can then participate in various transformation reactions. This process achieves regio- and stereo-selective activation of intramolecular C—H bonds without relying on conventional heteroatom directing groups, offering an attractive new strategy for the synthesis of molecules that are difficult to access using traditional methods and enabling rapid construction of complex molecular structures.
图1 “跨空间”金属迁移示意

Fig.1 “Through space” metal migration

As one of the important aspects in the study of metal migration, reactions based on aryl-to-alkenyl 1,4-palladium migration enable the highly stereoselective synthesis of a series of multisubstituted olefin compounds that are difficult to obtain by conventional methods. These reactions have potential applications in the fields of natural products, pharmaceuticals, and materials, thus attracting broad research interest. From a mechanistic perspective, following oxidative addition of an aryl halide to zero-valent palladium and formation of a divalent palladium complex, C—H activation of the alkenyl hydrogen can occur to generate a palladacycle species. This C—H activation step is generally believed to proceed via a concerted metallation-deprotonation (CMD) process under the influence of a base[4-5]. Protonation of the aryl C—Pd bond in the palladacycle species with selectivity leads to the formation of an alkenyl palladium species, completing the 1,4-palladium migration from the aryl to the alkenyl position. The resulting alkenyl palladium species can then react with various coupling reagents, enabling the stereoselective synthesis of multisubstituted olefin compounds (Figure 2).
图2 芳基向烯基1,4-钯迁移反应路径

Fig.2 Reaction pathway via aryl-to-vinylic 1,4-palladium migration reaction

From a mechanistic perspective, some challenging issues can also be observed in the aforementioned reactions, mainly including: (1) Both alkenylpalladium and arylpalladium species contain C(sp2)—Pd bonds and exhibit significant similarities in reactivity. Moreover, arylpalladium species form first; therefore, how to suppress the direct coupling reaction in situ is a fundamental issue. (2) The activation of alkenyl C—H bonds is involved in the system. Given the stability of C—H bonds, their efficient activation represents a challenge for the reaction. (3) Alkenylpalladium species are formed during the generation of o-haloarylalkene compounds. At the same time, the presence of both aryl halide and alkenyl moieties within these compounds enables them to act as coupling reagents, thereby undergoing self-coupling rather than coupling with externally added reagents.
There have been several review articles published on metal migration studies[6-10]. Given the importance of aryl-to-alkenyl 1,4-palladium migration reactions, this article will focus on recent research advances in this area.

2 Palladium Migration Reacts with sp2 Carbon Coupling Reagents

2.1 Alkenyl Coupling Reagents

The 1,3-conjugated diene structure is widely present in biologically active molecules[11-12], and its rich reactivity makes it an important multifunctional synthetic intermediate[13]. Currently, there are many synthetic methods available for constructing conjugated polyenes[12-14], however, the stereochemical control of their double bonds has remained a challenging issue in this field. Several strategies have been developed for controlling the stereochemistry of polyene structures, primarily achieved by increasing steric differences in the substrate structure or introducing heteroatom-containing directing groups[15-17].
In 2018, Hu et al.[18] achieved the synthesis of 1,3-dienes with high regioselectivity and stereoselectivity through a coupling reaction involving an aryl-to-vinyl 1,4-palladium migration intermediate and α,β-unsaturated carbonyl compounds (see Figure 3). Both biphosphine and monophosphine ligands were found to promote this reaction, generally yielding excellent regioselectivity and stereoselectivity. The highest yield was obtained using tris(o-methoxyphenyl)phosphine. A substrate scope study under optimal conditions revealed that the reaction exhibits broad substrate compatibility, including heterocyclic rings, carbonyl groups, and aldehyde groups. Kinetic isotope effect (KIE) measurements showed a KIE value of 3.2, indicating that C—H bond cleavage participates in the rate-determining step of the reaction. When the reaction scale was increased to gram level, comparable yields (81%) to small-scale reactions were still obtained. Moreover, the resulting 1,3-diene esters could be conveniently converted into acids and alcohols, further demonstrating the practicality of this method.
图3 缺电子烯烃偶联合成1,3-二烯

Fig.3 Synthesize 1,3-dienes via coupling with electron-deficient alkenes

On this basis, in 2021, Xue et al.[19] found that the corresponding coupling reaction could also occur when strongly electron-deficient olefins were replaced with more electron-neutral olefins (see Figure 4). Moreover, the reaction proceeded at lower temperatures and achieved excellent stereoselectivity.
图4 芳基或烷基烯烃偶联合成1,3-二烯

Fig.4 Synthesis of 1,3-dienes via coupling with aryl or alkyl-substituted alkenes

The conjugated triene structure, which contains three alternating double and single bonds, has a reduced energy gap between the ground state and excited state compared to dienes due to its extended conjugated system, thereby endowing it with unique chemical properties. Such structures are widely present in natural products[20] and optoelectronic materials[21-23], and also serve as common intermediates in organic synthesis[24-26].
Xue et al.[27] found that using 1,3-dienes as coupling reagents allows for stereoselective formation of conjugated trienes (Figure 5). This method bypasses the conventional requirement for phosphorus ylide methods to prepare alkenyl halides with specific geometries, offering greater flexibility and better stereochemical control, thereby simplifying the synthesis process and improving reaction efficiency and yield. The electronic nature of substituents on the aryl rings in diarylethylene substrates has little effect on the reaction yield, but steric effects significantly influence the reaction activity. Reactions proceed smoothly when one of the aryl rings is replaced by a heteroaryl, alkyl, nitrile, or ester group. Moreover, apart from aryl substitution, alkyl substitution in the 1,3-diene structure is also compatible.
图5 与二烯化合物偶联合成共轭三烯

Fig.5 Synthesis of conjugated trienes via coupling with 1,3-dienese

Besides olefins, alkenyl boron reagents can also serve as coupling agents for the highly stereoselective synthesis of polyenes. In 2020, Li et al.[28] employed alkenylborates to perform Suzuki-Miyaura coupling with alkenylpalladium species generated via 1,4-palladium migration (Figure 6). Under optimal conditions, o-alkenyl aryl bromides bearing different electronic properties and substituents underwent coupling with alkenylboronic esters in excellent yields. Moreover, various aryl- and alkyl-substituted vinylborates could also act as effective coupling partners in this reaction. Notably, by using 2,2-diaryl-substituted alkenylborates with different configurations, it was possible to synthesize tetraaryl-substituted 1,3-dienes, obtaining all four possible geometric isomers.
图6 与烯基硼酯偶联合成1,3-二烯

Fig.6 Synthesis of 1,3-dienes via coupling with alkenyl boronates

Synthesized polyaryl-substituted alkenes were found to exhibit aggregation-induced emission (AIE) effect. As shown in Figure 7, the synthesized molecule does not emit light in pure tetrahydrofuran solution under ultraviolet lamp irradiation, but emits deep blue fluorescence in a system containing 90% water by volume (fw), revealing its aggregation-induced emission properties (Figure 7a). Characterization using I/I0 curves and AIE curves indicated that when the water content increases to fw = 80 vol%, the system transitions from a non-emissive state to a fluorescent state. Further increasing the water content to fw = 90 vol%, thereby enhancing the aggregation state, results in a fivefold increase in emission intensity compared to that in tetrahydrofuran solution, demonstrating typical AIE characteristics (Figures 7b and 7c). Through precise stereochemical control and optical property testing of the obtained geometric isomers, significant differences in photoluminescence quantum efficiency among different isomers were observed. The aforementioned study effectively demonstrates the potential application value of the corresponding synthetic methodology in optoelectronic material research.
图7 代表性1,3-二烯分子的AIE特性

Fig.7 AIE properties of a representative 1,3-diene molecule

2.2 Aryl Coupling Reagents

Arylboron compounds are the most commonly used aryl coupling reagents in palladium-catalyzed reactions. The constructed multiaryl ethylenes often exhibit unique optical or electronic properties[29-31]. Therefore, the efficient synthesis of the corresponding molecules has also received significant attention.
Li et al.[28] found that various arylboron reagents could be applied to the 1,4-palladium migration/coupling reaction, but their structures significantly affected the regioselectivity and yield of the reaction. For example, highly reactive phenylboronic acid delivered a higher yield, but only achieved a regioselectivity of 2:1; in contrast, the more stable phenylboronic acid pinacol ester improved the regioselectivity to 93:7, yet afforded only a 29% yield. Selecting an appropriate arylboron reagent with suitable reactivity is crucial for this reaction, ensuring that it does not couple directly with the non-migrated palladium species due to excessively high activity, while maintaining sufficient reactivity to effectively couple with the migrated palladium species. After evaluation, boron glycol esters were identified as the optimal choice. Ligand selection represents another key factor in the reaction; tri-o-tolylphosphine, the most commonly used ligand in such migration reactions, still provided the best results. The substrate scope of the reaction was excellent, particularly accommodating arylboron esters that are compatible not only with functional groups such as aldehyde, amino, and ketone moieties, but also various heteroarylboron esters (Figure 8). Some of the synthesized molecules exhibited certain optical properties, demonstrating the potential application value of this methodology in optoelectronic materials.
图8 与芳基硼试剂偶联合成三取代烯烃

Fig.8 Synthesis of trisubstituted alkenes via coupling with arylboronates

Instead of using arylboron reagents, direct coupling with aryl C—H bonds would be a more efficient coupling method. Lin et al.[32] combined palladium migration with direct C—H bond activation of polyfluoroarenes, achieving polyfluoroarylation of vinylic palladium (Figure 9). In this reaction, the conventional trimethoxyphenylphosphine ligand was replaced with a bulkier tri-ortho-isopropoxyphenylphosphine ligand to obtain improved reaction yields (51% vs 79%). Various substituted ortho-brominated styrene compounds were successfully coupled with trifluoro- and tetrafluoroarene compounds, achieving moderate to excellent reaction yields along with complete regio- and stereocontrol. Additionally, functional groups such as esters, benzylic alcohols, and heterocycles were tolerated in the reaction. Mechanistic studies revealed a KIE value of 2.17 for the polyfluoroarene, whereas the KIE for substituted ortho-brominated styrenes was 1.21, suggesting that cleavage of the polyfluoroaryl C—H bond participates in the rate-determining step of the reaction, while cleavage of the vinylic C—H bond does not. Based on previous research reports, the authors proposed a plausible reaction pathway. According to this mechanism, the polyfluoroaryl C—H bond is activated by either the generated cyclopalladated species or the migratory-generated vinylic palladium species, subsequently forming an aryl-vinyl palladium complex, followed by reductive elimination to yield the desired product.
图9 与多氟芳烃C—H键直接偶联合成三取代烯烃

Fig.9 Synthesis of trisubstituted alkenes via direct coupling to polyfluoroarene C—H bonds

Tan et al.[33] applied a palladium/copper bimetallic synergistic catalytic strategy to achieve direct coupling between migratory alkenylpalladium and heteroaryl C—H bonds (see Figure 10). This reaction achieved innovative results in the following aspects: (1) The bimetallic synergistic catalytic strategy was first applied in palladium migration reactions. The ligand combination of Tol-BINAP and 1,10-phenanthroline delivered the best results. (2) Compared with the aryl bromides commonly used, aryl phenol triflates were employed in this reaction, further expanding the substrate scope of this field. (3) Monosubstituted ethylene structures could also undergo reaction smoothly in this system. In previous studies, such substrates were found difficult to realize palladium migration/coupling transformations. Based on this, cis-diarylethenes, triarylethenes, and tetraarylethenes could all be stereoselectively synthesized through this method. Mechanistic studies revealed that similar to coupling with polyfluoroarenes, the KIE for heteroarenes was 2.14, whereas the KIE for aryl ethenes was 0.99, indicating that cleavage of the alkenyl C—H bond is not the rate-determining step, while cleavage of the heteroaryl C—H bond participates in the rate-determining step. Optical property studies of the synthesized products revealed that certain molecules exhibited excellent AIE characteristics, providing promising examples for the potential application of this methodology in luminescent materials.
图10 钯/铜双金属协同与杂环C—H键直接偶联合成多取代取代烯烃

Fig. 10 Coupling with heteroarene C—H bonds in the Pd/Cu cooperative catalysis for the synthesis of polysubstituted alkenes

2.3 Diazo Coupling Reagent

Diazo compounds and N-sulfonyl hydrazone compounds are widely used as carbene precursors in transition metal-catalyzed coupling reactions[34-36]. Based on their previous studies of palladium-catalyzed coupling reactions of alkenyl bromides with diazo or N-sulfonyl hydrazone compounds for synthesizing tetrasubstituted allenes, Zhang et al.[37] further achieved 1,4-palladium migration/coupling to produce tetrasubstituted allenyl esters (Figure 11). In this reaction, the biphosphine ligand DPEPhos was crucial for the success of the reaction; other commonly used monophosphine and biphosphine ligands tested afforded yields of less than 38%. The KIE of aryl ene in this reaction reached 4.7, suggesting that it is involved in the rate-determining step. Allenes are prevalent in natural products, pharmaceuticals, and functional molecular materials[38-39], but the synthesis of tetrasubstituted allenes remains challenging. Therefore, the developed method serves as a valuable complement to existing approaches.
图11 与芳基重氮酸酯偶联合成四取代联烯

Fig.11 Synthesis of tetrasubstituted allenes via coupling with aryl diazoacetates

Lin et al.[40] subsequently applied N-aryl sulfonyl hydrazone compounds to achieve 1,4-palladium migration/coupling for the synthesis of tetrasubstituted allenes. At the same time, they found that using N-aryl sulfonyl hydrazones bearing α-hydrogens afforded 1,3-diene compounds under the same reaction conditions (Fig. 12). The addition of 2-fluorophenol significantly accelerated the aryl-to-vinyl 1,4-palladium migration process and suppressed the in situ generation of olefin compounds.
图12 与N-芳基磺酰腙化合物偶联合成四取代联烯和1,3-二烯

Fig.12 Synthesis of tetrasubstituted allenes and 1,3-dienes via coupling with N-aryl sulfonhydrazones

2.4 Carbonylation Coupling Reagents

There are currently many methods available for the efficient synthesis of substituted α,β-unsaturated carbonyl compounds[41,42,43-44], but further development is still required for stereoselective synthetic approaches. Li et al.[45] achieved a three-component coupling synthesis of α,β-unsaturated amide derivatives from o-bromoaryl vinyl compounds, CO, and amines based on a 1,4-palladium migration/coupling mechanism (Figure 13). The reaction allows for complete control over regioselectivity and stereoselectivity, and demonstrates good substrate generality; various o-bromoaryl vinyl compounds, aryl amines, and alkyl amines with different electronic properties and substitution positions are well tolerated under these reaction conditions. DFT calculations indicate that the energy barrier for alkene C—H bond activation through a CMD mechanism is 37.9 kcal·mol-1, which represents the rate-determining step of the reaction. This result is also consistent with the measured KIE value of 2.32.
图13 三组分偶联合成多取代α,β-不饱和酰胺

Fig.13 Synthesis of α,β-unsaturated amides via three-component coupling

Considering the experimental hazards associated with CO as a toxic gas, Ye et al. [46] utilized phenyl formate as a carbonyl source instead of CO to achieve the synthesis of highly stereoselective beta,beta-diaryl-substituted alpha,beta-unsaturated esters (Figure 14). Ligands and bases were both crucial for the reaction's yield, regioselectivity, and stereoselectivity. During reaction condition optimization studies, using 1,2-bis(diphenylphosphino)benzene (dppbz) as the ligand and tBuONa as the base achieved a 91% isolated yield along with regioselectivity and stereoselectivity exceeding 20:1. Mechanistic investigations revealed a KIE value of 1.08 for the aryl vinyl substrate, indicating that activation of the vinylic C-H bond was not the rate-determining step, which differs from the previously mentioned carbonylation work. Using the developed synthetic method as a key step, the authors conducted a formal synthesis of the clinical anti-cancer drug tamoxifen, demonstrating the potential value of this methodology in related pharmaceutical research (Figure 15).
图14 与甲酸苯酯偶联合成α,β-不饱和酯

Fig. 14 Synthesis of α,β-unsaturated esters via coupling with phenyl formats

图15 抗癌药物他莫昔芬的合成

Fig.15 Synthesis of the anticancer drug tamoxifen

3 Palladium Migration Reacts with sp3 Carbon Coupling Reagents

Compared with the reactions using sp2 coupling reagents, those employing sp3 coupling reagents are generally more challenging, and thus only two examples have been reported to date.
Wang et al.[47] employed cyclobutanol compounds as coupling reagents to achieve a 1,4-palladium migration/alkylation reaction. Cyclobutanol coordinates with palladium through ligand exchange, subsequently undergoing β-carbon elimination to introduce an alkyl group and reductive elimination to yield the target compound (Figure 16). Under optimal conditions (PCy3 as ligand and 2-fluorophenol as additive), the reaction exhibited good substrate generality, particularly achieving excellent regioselectivity (>20:1) and stereoselectivity. A parallel competition experiment showed a KIE value of 1.0, indicating that alkenyl C—H bond activation is not the rate-determining step in this reaction. DFT calculations revealed that the reaction's regioselectivity results from thermodynamic control, with 2-fluorophenol playing a significant role in both palladium migration and facilitating ligand exchange between cyclobutanol and palladium.
图16 与环丁醇偶联合成三取代烯烃

Fig.16 Synthesis of trisubstituted alkenes via coupling with cyclobutanols

Rocaboy et al.[48] connected alkyl or aryl structural fragments to terminal alkenes via a carbonyl group, enabling the aryl-to-alkenyl 1,4-palladium migration intermediate to further activate alkyl or aryl C—H bonds, thereby facilitating intramolecular ring closure to construct gamma-lactam or indanone structures (Figure 17). To ensure smooth reaction progress, this reaction employed a reaction system different from conventional reactions, mainly including: (1) using Pd(PCy3)2 as the catalyst instead of the commonly used Pd(OAc)2/ligand combination, and for some substrates, an additional 10 mol% PCy3 ligand was added to prevent catalyst decomposition; (2) employing Rb2CO3 as the base instead of common cesium or potassium salts; (3) adding 30 mol% acid PivOH as an additive along with the base; (4) conducting the reaction at a high temperature of 160 °C for 18 h. This method provides a highly efficient synthetic approach for preparing mono-, bi-, and tri-cyclic compounds containing gamma-lactam and indolinone structures.
图17 1,4-钯迁移/C(sp3)—H键活化构建γ-内酰胺或茚满酮

Fig.17 Synthesis of γ-lactams or indanones via 1,4-Pd migration/C(sp3)—H activation

The authors applied this method to achieve a five-step formal synthesis of the bioactive alkaloid (-)-pyrrolam A, isolated from the Streptomyces strain Streptomyces olivaceus, demonstrating its potential application in natural product synthesis (Fig. 18).
图18 天然生物碱Pyrrolam A的形式合成

Fig.18 Formal synthesis of the natural alkaloid pyrrolam A

4 Palladium migrates and reacts with sp carbon coupling reagents

1,3-Conjugated enynes are important structural motifs present in numerous bioactive compounds and functional material molecules.[49] Transition metal-catalyzed alkenylation of alkynes represents an efficient approach for synthesizing enynes; however, controlling the geometric configuration of the resulting double bond remains a challenging issue.
Chen et al.[50] discovered that triisopropylsilyl acetylene can undergo Sonogashira coupling with migratory-generated vinyl palladium, enabling the stereospecific synthesis of 1,3-enynes ( Figure 19). Under conventional catalytic systems based on Pd(OAc)2/tris(o-methoxyphenyl)phosphine ligand, further addition of TBAB, triethylamine, and 2-fluorophenol as additives allows the reaction to achieve optimal regioselectivity (11:1) and reaction yield (86%). Moreover, this reaction system does not involve copper; adding CuI actually reduces both the reaction yield and regioselectivity. Various ortho-bromoaryl ethylenes bearing different electronic and steric substituents can successfully couple with triisopropylsilyl acetylene, and heterocyclic compounds such as thiophene and pyridine are also well tolerated in this system. Unfortunately, replacing the triisopropylsilyl group with aryl or alkyl groups prevents the reaction from occurring.
图19 与端炔偶联合成1,3-烯炔

Fig.19 Synthesis of 1,3-enynes via coupling with terminal alkynes

Subsequently, Lin et al. [51] employed propargylic alcohol as a terminal alkyne precursor in the coupling reaction, effectively addressing the aforementioned issue of alkyne substrate expansion (Figure 20). Under basic conditions, aryl- or alkyl-substituted propargylic alcohols undergo retro-alkynylation, generating terminal alkynes that can undergo Sonogashira coupling with vinyl palladium species formed via 1,4-palladium migration, affording the desired 1,3-enynes. The bulky electron-rich ligand Sphos was found to be optimal for this reaction. 2-Fluorophenol was again used as an additive to promote the reaction. The reaction exhibited good substrate generality and provided regioselectivities greater than 20:1 along with exclusive geometric isomer selectivity. A parallel competition experiment yielded a KIE value of 1.01, indicating that alkenyl C—H bond activation is not the rate-determining step in this reaction.
图20 与炔丙醇偶联合成1,3-烯炔

Fig.20 Synthesis of 1,3-enynes via coupling with propargyl alcohols

5 Palladium migrates and reacts with heteroatom coupling reagents

Hu et al.[52] applied bis(pinacolato)diboron to undergo a Miyaura borylation reaction with the generated vinylpalladium species, achieving stereoselective synthesis of β,β-disubstituted vinylboronates (Figure 21). This work also represents the first example of a transformation based on aryl-to-alkenyl 1,4-palladium migration. Tris(p-methoxyphenyl)phosphine was identified as the preferred ligand for this reaction, enabling exclusive formation of the alkenyl boronate ester with a regioselectivity exceeding 20:1. The measured KIE value was 2.4, indicating that the alkenyl C—H bond activation participates in the rate-determining step of the reaction. A series of control experiments demonstrated that the presence of AcO- is crucial for the formation of the migration product, suggesting that the key alkenyl C—H bond activation step proceeds via a CMD mechanism, wherein AcO- serves as the essential internal base.
图21 与联硼酸频那醇酯偶联合成β,β-二取代乙烯基硼酯

Fig.21 Synthesis of β,β-disubstituted vinyl boronates via coupling with pinacol boronates

Chen et al.[53] applied phosphorus acid diesters as coupling reagents to achieve the synthesis of 2,2-disubstituted vinylphosphonates (Figure 22). Vinylphosphonates play significant roles in synthetic chemistry, pharmaceuticals, and materials science, and controlling the geometric configuration of their double bonds remains similarly challenging. Compared with other coupling reactions, the presence of a large amount of phosphorus-containing compounds often poisons the palladium catalyst, making the reaction difficult to proceed. The authors found that the dppp ligand and ether solvents were crucial for the success of this reaction, and the catalyst loading could be as low as 5 mol%. The reaction achieved exclusive regioselectivity (>20:1) for a single geometric isomer, consistently yielding excellent results. Additionally, phenyl phosphonates could also be successfully applied in this coupling reaction.
图22 与亚磷酸二酯偶联合成β,β-二取代烯基磷酸酯

Fig.22 Synthesis of β,β-disubstituted vinyl phosphonates via coupling with phosphite ester

6 Conclusion and Prospect

The controllable aryl-to-alkenyl 1,4-palladium migration provides a novel mode for the activation of alkenyl C–H bonds. Its coupling with various nucleophiles has become a powerful tool for the highly stereoselective synthesis of multisubstituted olefin compounds, demonstrating initial application value in synthetic chemistry, materials, and pharmaceutical research. Meanwhile, this study has also inspired related research, such as the recent rapid development of studies on aryl-to-alkenyl 1,4-rhodium[54-56] and nickel[57-59] migration reactions.
Although significant progress has been made in research, there are still some issues that require further exploration, mainly including:
(1) The use of ortho-haloaryl alkenes typically requires 1,1-disubstituted terminal alkenes to achieve the corresponding palladium migration transformation reactions. Although in some cases, monosubstituted terminal alkenes or 1,2-disubstituted alkenes can also undergo such reactions, there is still an urgent need for a more general catalytic system to enable other coupling reactions with these types of substrates.
(2) Existing studies all start with the oxidative addition of aryl halides to zero-valent palladium to form divalent pallidum. However, selective introduction of substituents onto the aromatic ring of o-haloarylalkene substrates often encounters difficulties. Therefore, combining research achievements in heteroatom-directed palladium-catalyzed C—H activation or decarboxylative coupling reactions to introduce new reaction initiation methods will further expand the scope of this reaction.
(3) Currently, some studies have been conducted on the reaction mechanism through control experiments, DFT calculations, and reactions with deuterated substrates. However, a more systematic investigation is still required to elucidate the effects of factors such as ligands, bases, and substrate steric structures on the reaction, in order to achieve rational design of the reaction.
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