Palladium-catalyzed asymmetric migratory diarylation of unactivated directing-group-free internal alkenes

Domain: chemistry
Published: 2026-01-05
Editorial outcome: minor_revision

Abstract
Enantioselective dicarbofunctionalization of alkenes is a powerful strategy for constructing functionalized sp³-rich molecules, yet it remains challenging for unactivated substrates lacking directing groups. While asymmetric multicomponent reactions catalyzed by d¹⁰ transition metals have advanced for activated alkenes, enantioselective multicomponent cross-coupling of unactivated alkenes, particularly enabling remote functionalization to stereoselectively generate the nonadjacent stereocenters, is still underdeveloped. Herein, we report a palladium-catalyzed asymmetric migratory dicarbofunctionalization of directing-group-free, trisubstituted unactivated alkenes. This method forges remote stereogenic centers, enabling both 1,3-diarylation and 1,4-diarylation with high enantioselectivity and diastereoselectivity. Mechanistic studies indicate a chain-walking process involving irreversible Pd-H migration, rationalizing the observed regiocontrol.

Introduction
Olefins are indispensable feedstocks for bulk chemicals, bioactive molecules, and functional materials, making the development of highly selective alkene transformations a central pursuit in organic synthesis. Among these, the stereoselective conversion of planar alkenes into diverse, highly functionalized three-dimensional sp³-hybridized molecules is particularly valuable. This is underscored by the well-established benefit of increased sp³-character in organic molecules for the success of clinical drug candidates1. Since Sigman’s foundational work2–4, asymmetric multicomponent cross-coupling reactions of alkenes catalyzed by d¹⁰ transition metals–specifically, dicarbofunctionalization–have emerged as a powerful synthetic strategy5–16. This approach enables the simultaneous incorporation of two distinct carbon fragments across the π-bond, facilitating rapid assembly of molecular complexity (Fig. 1). Prior efforts focused predominantly on reactive alkenes, such as acrylates, enamides, or styrenes2,17–30. In this realm, these functional groups regulate regioselectivity, also enhance reactivity, thus enabling facile migratory insertion of carbon-metal bonds or carbon-radical addition. However, enantioselective migratory dicarbofunctionalization of activated alkenes still remains scarce; only two cases include Sigman’s 1,1-diarylation of acrylates and our 1,3-diarylation of enamides17,31,32 (Fig. 1a, top). Despite these impressive advances, stereoselective intermolecular dicarbofunctionalization of unactivated alkenes remains largely underdeveloped, yet is highly desirable in organic synthesis13–16.

To accelerate the reactivity of unactivated alkenes, chelation-assisted strategies have been elegantly developed for chiral nickel-catalyzed 1,2-dicarbofunctionalization of unbiased alkenes33–38 (Fig. 1a, bottom). Representative examples include the Chu group’s enantioselective reductive 1,2-alkyl-alkenylation via five-membered nickellacycle formation33,34, the Engle group’s redox-neutral 1,2-diarylation, as well as Chen group’s reductive 1,2-diarylation through stereoselective migratory insertion35–37. However, enantioselective dicarbofunctionalization of the simple unactivated alkenes persisted as a formidable unmet challenge–with only one isolated example that the collaborative work between Koh and Shi presented the asymmetric 1,2-dicarbofunctionalization of light alkenes enabled by bulky chiral N-heterocyclic carbene-ligated nickel catalysis38. Beyond these advances, remote functionalization of unactivated alkenes is a distinct challenge, where successful examples could enable unconventional C–C bond formation at distant sites39–51. Notably, while several racemic 1,3-dicarbofunctionalization via nickel catalysis have been independently reported by Giri52,53, Zhao54, Martin55, and Shu group56, the asymmetric versions remained elusive, representing a critical synthetic gap.

Based on our continued research interest in d¹⁰ transition metal-catalyzed asymmetric dicarbofunctionalization17,18,57–64, we herein address these limitations by achieving the Pd-catalyzed asymmetric migratory dicarbofunctionalization of unactivated internal alkenes (Fig. 1b). This method accomplishes the enantioselective 1,3- and 1,4-dicarbofunctionalization of unactivated alkenes, forging remote stereogenic centers with high enantioselectivity; moreover, the broad reactivity without pre-installed directing group can overcome fundamental substrate constraints in alkene difunctionalization. This strategy enables expedient construction of 1,3- and 1,4-nonadjacent stereocenters with high enantioselectivity and diastereoselectivity, addressing a long-standing synthetic challenge in organic chemistry65–70. Mechanistic studies confirm a chain-walking process involving irreversible Pd-H migration, rationalizing the observed regiocontrol.

Results
Reaction optimization for diarylation of alkenes
Initial optimization of asymmetric remote dicarbofunctionalization employed non-activated trisubstituted alkene 1a, aryl diazonium salt 2a, and arylboronic acid 3a as model substrates with 5.0 mol% Pd(OAc)₂, 10 mol% (S)-Cy-Box (L1) as chiral ligand, and 16 mol% diethyl fumarate as achiral ligand in presence of 1.0 equivalent Ag₂CO₃ (Table 1). Pleasingly, this ligand-swap strategy proved effective for palladium-catalyzed 1,3-diarylation, affording the desired product 4a in 48% yield with 88% ee in DME (Table 1, entry 1). It should be noted that the addition of Ag₂CO₃ facilitates the transmetalation step18. Reactions in 1,4-dioxane showed comparable yield and marginally improved enantioselectivity (Table 1, entry 2), prompting further investigation of mixed DME/1,4-dioxane solvent ratios. Notably, a 1:3 DME/1,4-dioxane mixture delivered 4a in 57% yield and 92% ee (Table 1, entries 3–5). Subsequent screening of various substituted chiral BiOx ligands (Table 1, entries 6–10) revealed minimal impact on yield and enantioselectivity, with the isopropyl-substituted BiOx ligand L3 proving optimal, delivering 4a in 62% yield and 93% ee (Table 1, entry 7). Given the importance of additives in promoting efficient cross-coupling by accelerating reductive elimination, several fumarate diesters with different substituents (isopropyl A2, isobutyl A3, tert-butyl A4, phenyl A5, methyl A6) were evaluated (Table 1, entries 11-15). Diphenyl fumarate (A5) successfully facilitated the reaction, maintaining a slightly higher yield and similar enantioselectivity. Further optimization of the palladium catalyst identified [Pd(allyl)Cl] as optimal, furnishing 4a in 79% isolated yield with 93% ee (Table 1, entry 16). The current three-component cross-coupling protocol was not suitable for aryl halides as electrophiles.

Substrate scope of unactivated trisubstituted alkenes
With optimized conditions established, we evaluated the scope of unactivated trisubstituted alkenes (Fig. 2). Symmetrical kenes bearing a benzyl substituent were systematically investigated. Both electron-withdrawing and electron-donating para-substituted phenyl groups at the terminal site afforded products 4b–4e in moderate to good yields (61–72%) with excellent enantioselectivities (91–94% ee). The reaction tolerated a meta-fluoro-substituted phenyl counterpart, providing 4f in 40% yield and 91% ee. ortho-Substituted alkenes proved particularly effective, yielding 4g in 74% yield and 97% ee. Notably, an alkene bearing an acetal group was efficiently converted to the ketone-containing product 4h (55%, 94% ee), demonstrating direct ketone formation and expanding synthetic utility. Intriguingly, an unactivated alkene bearing methyl and ethyl substituents delivered the 1,3-diarylation product 4i bearing nonadjacent stereocenters in 44% isolated yield, 91% ee and >20:1 dr under minimally modified solvent conditions, highlighting the stereoselective Pd-H migration pathway. A trifluoromethyl-substituted alkene at the terminal position of a linear alkyl chain afforded 4j (43%, 91% ee). Diverse aromatic substituents, including methoxy (4k) and benzodioxole (4l) provided products in moderate yields with good stereoselectivity. It should be noted that all 1,3-diarylation proceeded with high stereoselectivity, with no diastereomers observed in the reaction mixture. However, the migratory diarylation of a linear 1,2-disubstituted alkene analog afforded the desired product only in very low yield, and the reaction failed entirely with fully substituted alkenes under the standard conditions. Further efforts will be devoted to addressing this limitation.

Substrate scope of aryl diazonium salts and arylboronic acids
Subsequently, we examined aryl diazonium salts and arylboronic acids, evaluating electronic effects and substituent positions (Fig. 3). para-Functionalized aryl diazonium salts afforded products 4m–4o in 45–62% yield with 90–94% ee. Naphthalene-derived (4p) and benzodioxole-derived (4q) diazonium salts gave good yields and enantioselectivities. Diazonium salts bearing meta-substituents (–Cl, –OBn, –OEt; 4r–4t) delivered products with excellent enantiocontrol (up to 94% ee). Arylboronic acids with diverse para-substituents (–tBu 4u, –OMe 4v, –TMS 4w, –CF₃ 4x) provided target products in high yields (up to 85%) with 94% ee. meta-Substituted arylboronic acids (4y–4ab) exhibited excellent enantioselectivities (up to 95% ee). Sterically encumbered biphenyl-2-ylboronic acid afforded 4ac in 63% yield and 96% ee. Electron-withdrawing substituents on the boronic acid (4ad) did not diminish stereoselectivity. The configuration of 4ae was unambiguously confirmed by X-ray crystallography, demonstrating stereoselective Pd-H chain walking process.

Beyond controlling stereoselectivity at the C-3 position, we investigated whether this migratory 1,n-diarylation strategy could extend to longer distances. Sigman and coworkers demonstrated that Pd–H species undergo stereoselective reinsertion into alkene intermediates in asymmetric remote Heck reactions4, a similar reactivity pattern also observed in our prior Pd-catalyzed diastereoselective 1,1-diarylation of 1,1-arylethylenes62. Applying standard conditions to unactivated trisubstituted alkene bearing a phenethyl substituent 5 smoothly delivered the 1,4-diarylation product 6a in 52% yield (Fig. 4). Notably, enantioselectivity decreased relative to the 1,3-diarylation (83% ee vs. 93% ee for 4a). Further optimization of chiral ligands, solvents, and palladium catalysts failed to improve enantiocontrol. This result suggests partial dissociation of the Pd–H species from the alkene intermediate occurs during extended migration. The reaction tolerated diverse arylboronic acids, affording products 6b–6i in 44–62% yield while establishing a new stereocenter at the C-4 position with 78–86% ee. It was noteworthy that this 1,4-diarylation also proceeds smoothly for the unsymmetric trisubstituted alkenes, delivering the desired product 6j with 89% ee and more than 20:1 dr. The presence of an aromatic ring at the alkene terminus is therefore critical for the observed 1,3- and 1,4-diarylation, an effect we attribute to the stabilization of a key benzylic palladium intermediate.

Mechanistic investigation
To further elucidate the impact of alkyl chain length on the stereoselective chain-walking process and the reversibility of Pd-H migration, preliminary mechanistic investigations were conducted (Fig. 5). While remote 1,n-diarylation of unactivated alkenes yielded products 8, 10, 12 in moderate isolated yields (45–57%), enantioselectivity declined significantly: 1,5-diarylation afforded product 8 in 26% ee, 1,6-diarylation yielded product 10 in 8% ee, and near-racemization occurred in 1,7-diarylation with only 4% ee (Fig. 5a). This erosion in enantioselectivity suggests insufficient weak interactions, such as potential coordination between phenyl ring at the terminal site of the unfunctionalized alkene intermediate with the palladium center during the long distance migration process such as 1,6- and 1,7-diarylations71, leading to undesired Pd-H dissociation. While the undesired dissociation rate may be slower than the re-insertion of Pd-H intermediate in the short-distance migration, such as 1,3-diarylation and 1,4-diarylation processes. Another possibility is a geometrically defined alkene intermediate cannot be formed when the stereogenic center is far from to the carbon-palladium site that undergoing the β-H elimination.

Deuterium-labeling experiments then probed the Pd-H chain-walking pathway: reaction of 5a-D (dideuterated at the benzylic position) gave 6a-D with >99% deuterium at C-3, and reaction of 7-D (dideuterated at C-4) resulted in regioselective deuterium migration (>99%) from C-4 to C-3, with no labeling at C-1, C-2, or C-5 (Fig. 5b). These results collectively indicate that the chain-walking migration proceed exclusively in a net forward direction toward the reaction site (eg. from C-4 to C-5 position), without detectable reversal. This regioselective, irreversible progression supports the proposed Pd–H insertion into the transient alkene intermediate, thereby preventing deuterium scrambling, while a behavior that stands in sharp contrast to the reversible chain-walking often observed in NiH-catalyzed cross-coupling chemistry42. Furthermore, a crossover experiment between deuterated 5a-D and non-deuterated 5b in the 1,4-diarylation yielded only 6a-D and 6k, with no crossover product, demonstrating that the Pd-H species remains tightly bound to the alkene chain during 1,4-migration, thereby preserving high enantioselectivity (Fig. 5c). Based on these findings and previous results17,18, a plausible mechanism for the 1,3-diarylation is proposed (Fig. 5d). The reaction is initiated with oxidative addition of Pd(0) catalyst with the aryl diazonium salts, forming intermediate Int-A. Stereoselective migratory insertion of Int-A across the alkene C=C bond yields Int-B. Syn β-hydride elimination from Int-B then produces Int-C42. The resulting Pd–H species undergoes chain-walking migration followed by stereoselective re-insertion into the alkene, affording the stabilized benzylic palladium species Int-D72,73. Subsequent transmetalation of Int-D with an arylboronic acid assisted by ligand exchange18, followed by reductive elimination promoted by the electronically deficient diphenyl fumarate, delivers the desired migratory product 4 and regenerates the Pd(0) catalyst.

In conclusion, we have developed a palladium-catalyzed enantioselective migratory dicarbofunctionalization of unactivated internal alkenes. This method enables facile 1,3- and 1,4-diarylation by integrating aryl diazonium salts and arylboronic acids as coupling partners. Notably, 1,3- and 1,4-non-contiguous stereocenters are formed with high enantio- and diastereoselectivity. Mechanistic studies indicate the migration proceeds via irreversible Pd–H insertion. Current efforts focus on tackling the unactivated fully substituted alkenes asymmetric cross-coupling for accessing non-contiguous quaternary stereocenters.

Methods
General procedure for diarylation of alkenes
To a dried 8-mL vial was charged with [Pd(allyl)Cl]₂ (2.5 mol %), L3 (10 mol%), A5 (16 mol%), Ag₂CO₃ (1.0 equiv), aryl diazonium salts (2.0 equiv), arylboronic acids (3.0 equiv) and alkene (1.0 equiv). After evacuated and backfilled nitrogen three times, DME/1,4-Dioxane (v/v=1/3, 0.5 M) or DCM/1,4-Dioxane (v/v=1/3, 0.5 M) was added. The reaction was allowed to stirred at 25 °C for 36~48h, and then the reaction was filtered with celite and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography to yield the diarylation product.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "The manuscript by Chen and coworkers have described a palladium-catalyzed asymmetric migratory diarylation of\nunactivated trisubstituted alkenes, thereby addressing a long-standing and formidable challenge in organic synthesis. The\nability to selectively construct 1,3- and 1,4-non-adjacent stereocenters from simple alkene feedstocks in a single catalytic\nstep, with excellent enantioselectivity and diastereoselectivity, represents a major methodological leap. The work is an\nelegant advancement in the field of asymmetric alkene functionalization. The work stands out for the utilization of a chain-\nwalking process to achieve remote difunctionalization, moving beyond the more common 1,2-selectivity that dominates the\nliterature on unactivated alkenes. The mechanistic proposal of an irreversible Pd-H migration, rationalizing the observed\nregiocontrol, is particularly insightful and well-supported by deuterium-labeling experiments, adding substantial depth to the\nstudy. By overcoming the fundamental constraints of substrate pre-functionalization and directing groups, this Pd-catalyzed\nsystem provides a versatile and powerful platform for the rapid assembly of complex, sp³-rich architectures. The broad\nsubstrate scope, encompassing a diverse range of aryl diazonium salts and arylboronic acids, further underscores its\nsynthetic utility and robustness. This work will undoubtedly inspire new thinking in asymmetric catalysis, particularly in the\nareas of remote functionalization and alkene chemistry, and I am pleased to recommend its publication in Nature\nCommunications after the following minor revisions are addressed.\n1. The most intriguing aspect of this study, beyond the synthetic achievement, is the observed erosion of enantioselectivity\nwith increasing alkyl chain length. The authors have performed excellent deuterium studies to elucidate the chain-walking\nprocess. The proposed mechanism presents a sharp and interesting contrast to the behavior often proposed or observed in\nsome NiH-catalyzed chain-walking systems. I suggest the authors include a brief discussion comparing their findings with\nthe recent advances in NiH-catalyzed remote functionalization, as this would highlight the unique mechanistic features of\ntheir Pd-catalyzed system and provide valuable context for the readers. Please also add relevant references to support this\ndiscussion.\n2. Regarding the deuterium-labeling experiments, the data shows the net forward migration. However, for products like 6a-D\nor 8-D, which contain two deuterium atoms, is there any experimental evidence or analysis to confirm the relative\nconfiguration of these two D atoms after the re-insertion step?\n3. All the substrate are trisubstiuted alkenes for the migratory diarylation. Please state the results (even if negative) for\nattempts using 1,2-disubstituted alkenes and fully substituted alkenes under the current catalytic system. A brief comment on\nthe reactivity or lack thereof for these alkene classes would be very helpful for readers looking to apply this methodology and\nunderstand its current limitations.\n4. The current title is slightly over-ambitious, as the chemistry demonstrated is specifically a diarylation. To better and more\naccurately reflect the work presented, I suggest modifying the title to: \"Palladium-Catalyzed Asymmetric Migratory\nDiarylation of Unactivated Directing-Group-Free Internal Alkenes\".\n5. For the diarylation products that contain two stereogenic centers (e.g., product 4i and 6j), the manuscript states they are\nobtained as a \"single diastereomer.\" Please explicitly state the diastereoselectivity (e.g., >20:1 dr) for these and any other\nrelevant compounds in the main text or captions of Figures 3 and 5 to provide quantitative clarity.\n6. The role of Ag₂CO₃ as an additive should be explicitly stated in the experimental section or provide a relevant citation.\n7. A very recent paper (Nat. Chem. doi: 10.1038/s41557-025-01936-3) on 1,3-hydrofunctionalizationof trisubstituted alkenes\nshould be cited properly in the revised manuscript.\n8. Several typographical errors should be corrected throughout the manuscript. For instance:\nPage 4: \"independantly reported\" should be corrected to \"independently reported\".\nPage 12: \"While the undesired disscociate rate\" should be corrected to \"While the undesired dissociation rate\".\nOverall, a careful proofreading of the entire manuscript is recommended.", "reviewer_2": "Prof. Chen and his group have developed a palladium-catalyzed enantioselective migratory dicarbofunctionalization of\nunactivated internal alkenes. This method enables efficient 1,3- and 1,4-diarylation by employing aryl diazonium salts and\narylboronic acids as coupling partners, leading to the formation of 1,3- and 1,4-non-contiguous stereocenters with high\nenantio- and diastereoselectivity. Mechanistic studies suggest that the migration proceeds via irreversible Pd-H\ninsertion. Overall, this manuscript is suitable for publication in Nature Communications after\nappropriate revisions.\n(1) The text describes that an unactivated alkene bearing a prochiral carbon yields 1,3-diarylation products containing\nnonadjacent stereocenters as a single diastereomer. To aid clarity, it would be helpful to explicitly indicate the d.r. values\n(eg., >25:1) for products such as 4i, 4j, 4k, 4l, 4t, 4ad, 4ae, and 6j, which feature nonadjacent stereocenters.\n(2) Fumarate is employed as the ligand under the standard reaction conditions. It would be valuable to clarify whether any\nbackground reaction involving fumarate occurs during the process.\n(3) In this study, alkene substrates (e.g., 1, 5) bearing primarily benzyl substituents have been systematically investigated.\nCould the proposed reaction intermediate Int-D in the mechanism therefore be a benzylpalladium species (Adv. Synth.\nCatal. 2021, 363, 587.)?\n(4) While Pd(II) species can typically be generated from Pd(0) using Ag₂CO₃ as an oxidant, it remains unclear how Pd(0)\nforms under the reported oxidative conditions. Further clarification on this aspect would be beneficial.", "reviewer_3": "In this paper, Chen and co-workers reported a reaction system that allows for the enantioselective migratory 1,3- and 1,4-\ndicarbofunctionalization of trisubstituted alkenes. The methodology employs arylboronic acid and diazonium salts as\ncoupling partner, and a combination of ligands to facilitate the chain-walking product in good yields and high ee. Both\nelectron-withdrawing and electron-donating functional groups can be tolerated. Mechanistic studies supported an\nirreversible chain-walking pathway. Although the scope of this methodology is obviously limited, this work represents an\nadvance and may open new directions in the field of asymmetric migratory dicarbofunctionalization. The paper could be\nsuitable for publication in Nature Communications after the following issues are clearly addressed.\n(1) As a follow-up work to Ref. 18, this work uses an almost identical catalytic system, only differing in the alkene substrate\nclass. Upon reading Ref. 18, I noticed that compound 4j, which bearing a similar alkene type as in this current study, did not\nundergo chain-walking. The authors should discuss in detail the limitations of the alkene scope in this system: which\nalkenes are competent for chain-walking and which are not? Such clarification will provide valuable guidance to readers\nseeking to apply this methodology in their own synthesis.\n(2) The functional groups reported in this work appears rather narrow. Only a few categories are represented: alkyls,\naryls, ethers, esters, TMS, and fluorides. All the examples are permutations of these groups. How about heterocyclic\nsubstitutions? And it should be noted that all E, non-exocyclic alkenes showed yields below 50%. How about endocyclic\nalkenes or Z, non-exocyclic alkenes?\n(3) Figure 1A is difficult to interpret in its current form. Instead of listing the people names, I prefer to have the actual structure\nof C1, C2, FG, Ar, EWG, DG. If space is limited in this figure, please at least put the reference numbers next to each name so\nreaders can easily locate the corresponding work. For example, it took me some time to identify the top-right 1,3-DCF work,\nwhich seems to be reference 17. However, Ref. 17 used heteroatom-activated alkenes, not the same DG-strategy\nused by Chu, Engle, and Chen in the second row. So, I suggest showing the actual structures, not just “DG”.\n(4) The rationale for the ligand-swap strategy should be explained in detail. What happens if the second ligand is omitted?\nSimilarly, the function of Ag₂CO₃ should be discussed. Additionally, what is the outcome if diazonium salt were replaced by\nan aryl halide? These details will improve mechanistic understanding and help readers appreciate the design logic behind\nthe system.\n(5) For the mechanism, how did the authors demonstrate that the ligand-swap indeed occurs? Additionally, what is the\nexplanation for the observed formation of a single diastereomer? Please provide experimental or cite appropriate literatures\nto support these mechanistic conclusions.\n(6) For longer-chain examples, the authors attribute reduced ee to potential phenyl-palladium\ncoordination. Please clarify which type of interaction is proposed.\nA few other typos or mistakes that I have found:\n(7) Some references were not cited at the most appropriate locations. For example “Engle group’s redox-neutral 1,2-\ndiarylation, as well as Chen group’s reductive 1,2-diarylation through stereoselective migratory insertion [35]” It should be\nFef. [35-37] here.\n(8) Some words should be italic, such as heteroatom and ee\n(9) In figure 6d, the rotation product of intB appears to be incorrect.\n(10) In SI, the name of compound 4a is incorrect. Should be S instead of R. Its mass is also incorrect. Please do a careful\nproofreading of the SI to make sure there is no similar mistakes."}, "author_response": "The detailed response to the reviewers’ comments:\nReviewer: 1\nRecommendation: Publish in Nature Communications after minor revisions.\nComments:\nThe manuscript by Chen and coworkers have described a palladium-catalyzed asymmetric\nmigratory diarylation of unactivated trisubstituted alkenes, thereby addressing a long-standing and\nformidable challenge in organic synthesis. The ability to selectively construct 1,3- and 1,4-non-\nadjacent stereocenters from simple alkene feedstocks in a single catalytic step, with excellent\nenantioselectivity and diastereoselectivity, represents a major methodological leap. The work is an\nelegant advancement in the field of asymmetric alkene functionalization. The work stands out for\nthe utilization of a chain-walking process to achieve remote difunctionalization, moving beyond the\nmore common 1,2-selectivity that dominates the literature on unactivated alkenes. The mechanistic\nproposal of an irreversible Pd-H migration, rationalizing the observed regiocontrol, is particularly\ninsightful and well-supported by deuterium-labeling experiments, adding substantial depth to the\nstudy. By overcoming the fundamental constraints of substrate pre-functionalization and directing\ngroups, this Pd-catalyzed system provides a versatile and powerful platform for the rapid assembly\nof complex, sp³-rich architectures. The broad substrate scope, encompassing a diverse range of\naryl diazonium salts and arylboronic acids, further underscores its synthetic utility and robustness.\nThis work will undoubtedly inspire new thinking in asymmetric catalysis, particularly in the areas of\nremote functionalization and alkene chemistry, and I am pleased to recommend its publication in\nNature Communications after the following minor revisions are addressed.\nResponse: We sincerely thank reviewer 1 for the very positive comments and recommendation on\npublication.\n1. The most intriguing aspect of this study, beyond the synthetic achievement, is the observed\nerosion of enantioselectivity with increasing alkyl chain length. The authors have performed\nexcellent deuterium studies to elucidate the chain-walking process. The proposed mechanism\npresents a sharp and interesting contrast to the behavior often proposed or observed in some NiH-\ncatalyzed chain-walking systems. I suggest the authors include a brief discussion comparing their\nfindings with the recent advances in NiH-catalyzed remote functionalization, as this would highlight\nthe unique mechanistic features of their Pd-catalyzed system and provide valuable context for the\nreaders. Please also add relevant references to support this discussion.\nResponse: We thank the reviewer for the insightful suggestion regarding the comparison between\nPdH and NiH chemistry. In NiH-catalyzed systems, the chain-walking process is generally\nreversible, whereas we did not observe such reversibility in our palladium-based system.\nFurthermore, the 3d-character of nickel intermediates enables the benzylic nickel species to\npotentially undergo single-electron transfer pathways, whereas palladium typically follows a two-\nelectron transmetalation mechanism.\nIn the revised manuscript, we have cited a comprehensive review on NiH-catalyzed remote\nfunctionalization (Acc. Chem. Res. 2022, 55, 3519–3536) as reference 71 and added the following\nstatement: “This regioselective, irreversible progression supports the proposed Pd–H insertion into\nthe transient alkene intermediate, thereby preventing deuterium scrambling, while a behavior that\nstands in sharp contrast to the reversible chain-walking often observed in NiH-catalyzed cross-\ncoupling chemistry.71”\n2. Regarding the deuterium-labeling experiments, the data shows the net forward migration.\nHowever, for products like 6a-D or 8-D, which contain two deuterium atoms, is there any\nexperimental evidence or analysis to confirm the relative configuration of these two D atoms after\nthe re-insertion step?\nResponse: Thanks for reviewer 1’s suggestions. Based on the established mechanism of β-H\nelimination and reinsertion, we propose that the two deuterium atoms in the product adopt a trans\nrelative configuration following the reinsertion step, as illustrated in the scheme below.\nWe have obtained the crystal of the deuterated product 6a-D and the result has been included in\nthe Supporting Information (Crystallographic Data).; However, X-ray diffraction cannot distinguish\nbetween hydrogen and deuterium atoms, making this technique unsuitable for configurational\nassignment. Furthermore, since the compound is linear, the coupling constants in the H¹ NMR\nspectrum do not provide diagnostic information to unambiguously determine the relative\nconfiguration of the deuterium atoms.\ndeuterated product 6a-D (CCDC 2475482)\n3. All the substrate are trisubstiuted alkenes for the migratory diarylation. Please state the results\n(even if negative) for attempts using 1,2-disubstituted alkenes and fully substituted alkenes under\nthe current catalytic system. A brief comment on the reactivity or lack thereof for these alkene\nclasses would be very helpful for readers looking to apply this methodology and understand its\ncurrent limitations.\nResponse: Thanks for reviewer 1’s suggestions. When a linear 1,2-disubstituted alkene analogue\nwas tested under the standard conditions, the desired product was obtained, albeit in very low yield.\nIn contrast, the reaction proved incompatible with fully substituted alkenes, and no migratory\ndiarylation product was detected under the same catalytic system. These results have been\nincluded in the Supporting Information (Table S5).\nIn the revised manuscript, we added the following descriptions: “However, the migratory diarylation\nof a linear 1,2-disubstituted alkene analogue afforded the desired product only in very low yield,\nand the reaction failed entirely with fully substituted alkenes under the standard conditions. Further\nefforts will be devoted to addressing this limitation.”\n4. The current title is slightly over-ambitious, as the chemistry demonstrated is specifically a\ndiarylation. To better and more accurately reflect the work presented, I suggest modifying the title\nto: \"Palladium-Catalyzed Asymmetric Migratory Diarylation of Unactivated Directing-Group-Free\nInternal Alkenes\".\nResponse: Thanks for reviewer 1’s suggestions. It has been modified as suggested.\n5. For the diarylation products that contain two stereogenic centers (e.g., product 4i and 6j), the\nmanuscript states they are obtained as a \"single diastereomer.\" Please explicitly state the\ndiastereoselectivity (e.g., >20:1 dr) for these and any other relevant compounds in the main text or\ncaptions of Figures 3 and 5 to provide quantitative clarity.\nResponse: Thanks for reviewer 1’s suggestions. These have been corrected.\n6. The role of Ag₂CO₃ as an additive should be explicitly stated in the experimental section or\nprovide a relevant citation.\nResponse: Thanks for reviewer 1’s suggestions. Based on our previous studies (J. Am. Chem. Soc.\n2024, 146, 16892), Ag₂CO₃ can accelerate the transmetalation of arylboronic acids.\nWe added it in the revised manuscript: “It should be noted that the addition of Ag₂CO₃ facilitates\nthe transmetalation step.18”\n7. A very recent paper (Nat. Chem. doi: 10.1038/s41557-025-01936-3) on 1,3-\nhydrofunctionalization of trisubstituted alkenes should be cited properly in the revised manuscript.\nResponse: Thanks for reviewer 1’s suggestions. It has been cited as ref. 70 in the revised\nmanuscript.\n8. Several typographical errors should be corrected throughout the manuscript. For instance:\nPage 4: \"independantly reported\" should be corrected to \"independently reported\".\nPage 12: \"While the undesired disscociate rate\" should be corrected to \"While the undesired\ndissociation rate\".\nResponse: Thanks for reviewer 1’s suggestions. These have been corrected.\nReviewer: 2\nRecommendation: Suitable for Nature Communication after minor revisions.\nComments:\nProf. Chen and his group have developed a palladium-catalyzed enantioselective migratory\ndicarbofunctionalization of unactivated internal alkenes. This method enables efficient 1,3- and 1,4-\ndiarylation by employing aryl diazonium salts and arylboronic acids as coupling partners, leading to\nthe formation of 1,3- and 1,4-non-contiguous stereocenters with high enantio- and\ndiastereoselectivity. Mechanistic studies suggest that the migration proceeds via irreversible Pd-H\ninsertion. Overall, this manuscript is suitable for publication in Nature Communications after\nappropriate revisions.\nResponse: We sincerely thank reviewer 2 for the very positive comments and recommendation on\npublication.\n(1) The text describes that an unactivated alkene bearing a prochiral carbon yields 1,3-diarylation\nproducts containing nonadjacent stereocenters as a single diastereomer. To aid clarity, it would be\nhelpful to explicitly indicate the d.r. values (eg., >25:1) for products such as 4i, 4j, 4k, 4l, 4t, 4ad,\n4ae, and 6j, which feature nonadjacent stereocenters.\nResponse: Thanks for reviewer 2’s suggestions. These have been explicitly indicated.\n(2) Fumarate is employed as the ligand under the standard reaction conditions. It would be\nvaluable to clarify whether any background reaction involving fumarate occurs during the process.\nResponse: Thanks for reviewer 2’s suggestions. The fumarate could undergoes a certain\nbackground reaction with aryl diazonium salts under optimal conditions, but only trace products\nwere observed.\n(3) In this study, alkene substrates (e.g., 1, 5) bearing primarily benzyl substituents have been\nsystematically investigated. Could the proposed reaction intermediate Int-D in the mechanism\ntherefore be a benzylpalladium species (Adv. Synth. Catal. 2021, 363, 587.)?\nResponse: Thanks for reviewer 2’s suggestions. We completely agree reviewer 2’s comments on\nthe stablized benzylpalladium intermediate to promote the chain-walking process. We added this\nexcellent review as reference 73 in the revised manuscript.\n(4) While Pd(II) species can typically be generated from Pd(0) using Ag₂CO₃ as an oxidant, it\nremains unclear how Pd(0) forms under the reported oxidative conditions. Further clarification on\nthis aspect would be beneficial.\nResponse: Thanks for reviewer 2’s suggestions. The formation of Pd(0) could be generate through\nthe oxidative homocoupling of aryl boronic acid to initiate the catalytic cycle.\nReviewer: 3\nRecommendation: Suitable for publication in Nature Communications after the following issues are\nclearly addressed.\nComments:\nIn this paper, Chen and co-workers reported a reaction system that allows for the enantioselective\nmigratory 1,3- and 1,4-dicarbofunctionalization of trisubstituted alkenes. The methodology employs\narylboronic acid and diazonium salts as coupling partner, and a combination of ligands to facilitate\nthe chain-walking product in good yields and high ee. Both electron-withdrawing and electron-\ndonating functional groups can be tolerated. Mechanistic studies supported an irreversible chain-\nwalking pathway. Although the scope of this methodology is obviously limited, this work represents\nan advance and may open new directions in the field of asymmetric migratory\ndicarbofunctionalization. The paper could be suitable for publication in Nature Communications\nafter the following issues are clearly addressed.\nResponse: We sincerely thank reviewer 3 for the very positive comments and recommendation on\npublication.\n(1) As a follow-up work to Ref. 18, this work uses an almost identical catalytic system, only differing\nin the alkene substrate class. Upon reading Ref. 18, I noticed that compound 4j, which bearing a\nsimilar alkene type as in this current study, did not undergo chain-walking. The authors should\ndiscuss in detail the limitations of the alkene scope in this system: which alkenes are competent for\nchain-walking and which are not? Such clarification will provide valuable guidance to readers\nseeking to apply this methodology in their own synthesis.\nResponse: Thanks for reviewer 3’s suggestions. The preference for the formation of benzylic\npalladium intermediate is the cucial factor for the migrative or direct diarylation, which also governs\nthe regioselectivity of this dicarbonfunctionalization chemistry.\nWe added the follwing statement in the revised manusript: “The presence of an aromatic ring at the\nalkene terminus is therefore critical for the observed 1,3- and 1,4-diarylation, an effect we attribute\nto the stabilization of a key benzylic intermediate.”\n(2) The functional groups reported in this work appears rather narrow. Only a few categories are\nrepresented: alkyls, aryls, ethers, esters, TMS, and fluorides. All the examples are permutations of\nthese groups. How about heterocyclic substitutions? And it should be noted that all E, non-\nexocyclic alkenes showed yields below 50%. How about endocyclic alkenes or Z, non-exocyclic\nalkenes?\nResponse: Thanks for reviewer 3’s suggestions. We have tried some aryl diazonium salts and\narylboronic acids with different heterocyclic substitutions, such as -thiophene, -furan and -pyridine,\nbut no desired product could be observed at TLC and crude 1H NMR under the standard condition.\nWe added this result in supporting information table S6.\nWe synthesized the endocyclic alkene of 1-(cyclohex-1-en-1-ylmethyl)-4-methoxybenzene as the\nstarting material, could only afford the desired product in very low yield and enantioselectivity but\nhigh diastereoselectivity as shown below. We added this result in supporting information table S5.\nUnfortunately, due to the instability of Z, non-exocyclic alkenes, we have tried many methods but\nfailed to afford the desired alkenes. Further detailed studies on the details of unactivated\ntrisubstituted and fully substituted alkenes are currently underway in our laboratory.\n(3) Figure 1A is difficult to interpret in its current form. Instead of listing the people names, I prefer\nto have the actual structure of C1, C2, FG, Ar, EWG, DG. If space is limited in this figure, please at\nleast put the reference numbers next to each name so readers can easily locate the corresponding\nwork. For example, it took me some time to identify the top-right 1,3-DCF work, which seems to be\nreference 17. However, Ref. 17 used heteroatom-activated alkenes, not the same DG-strategy\nused by Chu, Engle, and Chen in the second row. So, I suggest showing the actual structures, not\njust “DG”.\nResponse: Thanks for reviewer 3’s suggestions. The top right of 1,3-DCF is indeed the\nheteroatom-activated alkene-enamide, therefore we place it in the catalog of activated alkene. To\nmake the layout of Fig 1 clearer, we draw the enamide in top right and added the reference next to\neach transformation, thank you for the great suggestion!\n(4) The rationale for the ligand-swap strategy should be explained in detail. What happens if the\nsecond ligand is omitted? Similarly, the function of Ag₂CO₃ should be discussed. Additionally, what\nis the outcome if diazonium salt were replaced by an aryl halide? These details will improve\nmechanistic understanding and help readers appreciate the design logic behind the system.\nResponse: Thanks for reviewer 3’s suggestions. Based on our previous studies (J. Am. Chem. Soc.\n2024, 146, 16892), Ag₂CO₃ can accelerate the transmetalation of arylboronic acids.\nUnfortunately, our chemistry is not suitable for the aryl halides.\nIn the revised manuscript, we added these informations: “It should be noted that the addition of\nAg₂CO₃ facilitates the transmetalation step.18” “The current three-component cross-coupling\nprotocol was not suitable for aryl halides as electrophiles.”.\n(5) For the mechanism, how did the authors demonstrate that the ligand-swap indeed occurs?\nAdditionally, what is the explanation for the observed formation of a single diastereomer? Please\nprovide experimental or cite appropriate literatures to support these mechanistic conclusions.\nResponse: Thanks for reviewer 3’s suggestions. Experimentally, no desired product was formation\nwith the omission of either chiral or achiral ligand. We performed the detailed DFT calculation on\nour previous 1,2-diarylation chemistry (ref. 18). We also have observed the similar 1,3-diarylation\nof activated alkenes (ref. 17). Therefore, we recited the refs. 17-18 in the mechanism study part in\nthe revised manscript as show: “Based on these findings and previous results17,18, a plausible\nmechanism for the 1,3-diarylation is proposed (Fig. 6d).”.\n(6) For longer-chain examples, the authors attribute reduced ee to potential phenyl-palladium\ncoordination. Please clarify which type of interaction is proposed.\nResponse: We thank the reviewer 3 for raising this point. We propose that an arene–palladium\ninteraction may be involved; however, definitive experimental evidence to confirm the exact nature\nof this coordination is currently lacking. Therefore, we have outlined several plausible mechanistic\npathways that could account for the erosion of enantioselectivity observed in the longer-chain\nmigratory diarylation reactions.\nOther typos or mistakes corrections:\n(7) Some references were not cited at the most appropriate locations. For example “Engle group’s\nredox-neutral 1,2-diarylation, as well as Chen group’s reductive 1,2-diarylation through\nstereoselective migratory insertion [35]” It should be Fef. [35-37] here.\nResponse: Thanks for reviewer 3’s suggestions. These have been corrected in the revised\nmanuscript.\n(8) Some words should be italic, such as heteroatom and ee\nResponse: Thanks for reviewer 3’s suggestions. These have been corrected.\n(9) In figure 6d, the rotation product of intB appears to be incorrect.\nResponse: Thanks for reviewer 3’s suggestions. These have been corrected.\n(10) In SI, the name of compound 4a is incorrect. Should be S instead of R. Its mass is also\nincorrect. Please do a careful proofreading of the SI to make sure there is no similar mistakes.\nResponse: Thanks for reviewer 3’s suggestions. These have been corrected and the Supporting\nInformation has been carefully checked."}, {"round": 2, "reviewer_comments": {"reviewer_1": "Having reviewed the authors' revisions, it was found that almost all my previous concerns have been adequately addressed.\nThus, this reviewer is pleased to recommend the acceptance of this manuscript.", "reviewer_2": "With the questions having been satisfactorily addressed by the authors, I recommend the manuscript for publication in\nNature Communications.", "reviewer_3": "The authors have addressed all of my questions except Question 6. However, their explanation remains unclear. It seems\nthey list several possible reasons without indicating which is most likely, and these possibilities are not supported by\nexperimental evidence or prior literature, reducing the clarity and credibility of the response. The paper will be suitable for\npublication after this section is clarified and polished."}, "author_response": "The detailed response to the reviewers’ comments:\nReviewer: 1\nRecommendation: Publish directly in Nature Communications.\nComments:\nHaving reviewed the authors' revisions, it was found that almost all my previous concerns have\nbeen adequately addressed. Thus, this reviewer is pleased to recommend the acceptance of this\nmanuscript.\nResponse: We sincerely thank reviewer 1 for the recommendation on publication.\nReviewer: 2\nRecommendation: Publish directly in Nature Communications.\nComments:\nWith the questions having been satisfactorily addressed by the authors, I recommend the\nmanuscript for publication in Nature Communications.\nResponse: We sincerely thank reviewer 2 for the recommendation on publication.\nReviewer: 3\nRecommendation: Suitable for publication in Nature Communications after the following issue is\nclarified and polished.\nComments:\nThe authors have addressed all of my questions except Question 6. However, their explanation\nremains unclear. It seems they list several possible reasons without indicating which is most likely,\nand these possibilities are not supported by experimental evidence or prior literature, reducing the\nclarity and credibility of the response. The paper will be suitable for publication after this section is\nclarified and polished.\nResponse: We sincerely thank reviewer 3 for the very positive comments and recommendation on\npublication.\n(6) For longer-chain examples, the authors attribute reduced ee to potential phenyl-palladium\ncoordination. Please clarify which type of interaction is proposed.\nResponse: We thank the reviewer 3 for raising this point. We tend to be the palladium-arene\ninteraction in 1,3- and 1,4-diarylation process that the alkyl palladium center after migratory\ninsertion of alkene is close to the terminal arene, wherein a palladium intermediate in norbornene\nchemistry was isolated by Catellani (JACS, 2002, 124, 4336). We added this reference in the\nrevised manuscript."}]

Decision letter