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 work2,3,4, asymmetric multicomponent cross-coupling reactions of alkenes catalyzed by d¹⁰ transition metals–specifically, dicarbofunctionalization–have emerged as a powerful synthetic strategy5,6,7,8,9,10,11,12,13,14,15,16. 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 styrenes2,17,18,19,20,21,22,23,24,25,26,27,28,29,30. 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 synthesis13,14,15,16.

Fig. 1: Overview of transition metal-catalyzed enantioselective intermolecular dicarbofunctionalization of alkenes.
figure 1

a Enantioselective Dicarbofunctionalization (DCF) of Acyclic Alkenes. b Enantioselective 1,3 and 1,4-Diarylation of Unactivated Trisubstituted Acyclic Alkenes (this work).

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To accelerate the reactivity of unactivated alkenes, chelation-assisted strategies have been elegantly developed for chiral nickel-catalyzed 1,2-dicarbofunctionalization of unbiased alkenes33,34,35,36,37,38 (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 insertion35,36,37. 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 sites39,40,41,42,43,44,45,46,47,48,49,50,51. 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 dicarbofunctionalization17,18,57,58,59,60,61,62,63,64, 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 chemistry65,66,67,68,69,70. Mechanistic studies confirm a chain-walking process involving irreversible Pd-H migration, rationalizing the observed regiocontrol.

Results and discussion

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]2 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.

Table 1 Reaction optimization
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Substrate scope of unactivated trisubstituted alkenes

With optimized conditions established, we evaluated the scope of unactivated trisubstituted alkenes (Fig. 2). Symmetric alkenes 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.

Fig. 2: Substrate scope of unactivated trisubstituted alkenes.
figure 2

Reaction conditions: alkene 1 (1.0 equiv, 0.20 mmol), aryl diazonium salt 2a (2.0 equiv, 0.40 mmol), arylboronic acid 3a (3.0 equiv, 0.60 mmol), [Pd(allyl)Cl]2 (2.5 mol %, 0.005 mmol), L3 (10 mol %, 0.02 mmol), A5 (16 mol %, 0.032 mmol), and Ag2CO3 (1.0 equiv, 0.20 mmol) in DME/1,4-Dioxane (0.4 mL (v/v = 1/3), 0.5 M) at 25 °C. Isolated yields were reported, and the ee values were determined by chiral HPLC. aDCM/1,4-Dioxane (0.4 mL (v/v = 1/3), 0.5 M) was used.

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Substrate scope of aryldiazonium 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.

Fig. 3: Substrate scope of aryl diazonium salts and arylboronic acids.
figure 3

Reaction conditions: alkene 1 (1.0 equiv, 0.20 mmol), aryl diazonium salt 2 (2.0 equiv, 0.40 mmol), arylboronic acid 3 (3.0 equiv, 0.60 mmol), [Pd(allyl)Cl]2 (2.5 mol %, 0.005 mmol), L3 (10 mol %, 0.02 mmol), A5 (16 mol %, 0.032 mmol), and Ag2CO3 (1.0 equiv, 0.20 mmol) in DME/1,4-Dioxane (0.4 mL (v/v = 1/3), 0.5 M) at 25 oC. Isolated yields were reported and the ee values were determined by chiral HPLC. aDCM/1,4-Dioxane (0.4 mL (v/v = 1/3), 0.5 M) was used.

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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 aryl boronic 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.

Fig. 4: Palladium-catalyzed 1,4-diarylation of unactivated trisubstituted alkenes.
figure 4

Reaction conditions: alkene 5 (1.0 equiv, 0.20 mmol), aryl diazonium salt 2a (2.0 equiv, 0.40 mmol), arylboronic acid 3 (3.0 equiv, 0.60 mmol), [Pd(allyl)Cl]2 (2.5 mol %, 0.005 mmol), L3 (10 mol %, 0.02 mmol), A5 (16 mol %, 0.032 mmol), and Ag2CO3 (1.0 equiv, 0.20 mmol) in DME/1,4-Dioxane (0.4 mL (v/v = 1/3), 0.5 M) at 25 °C. Isolated yields were reported, and the ee values were determined by chiral HPLC.

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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 maybe 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.

Fig. 5: Mechanistic studies.
figure 5

a Effect of the alkyl chain length. b Deuterium-labeling experiment. c Cross-over experiment. d Proposed mechanism.

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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 proceeds 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 benzyl 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 ~ 48 h, 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.