Alkyne migratory functionalization via C(sp³)–C(sp³) bond transposition

Abstract

Different from broadly studied metal walking strategy as a powerful way to realize remote C–H activation of alkenes, process for alkyne walking and functionalization remains unexplored. Similarly, alkyne hydrofunctionalization exclusively focuses on in situ transformation, while related remote protocol is unknown. Here we describe a proof-of-concept study on migratory alkyne functionalization. Three types of alkynes and two types of nucleophiles are adopted to realize the migratory hydroalkylation and hydroamination of alkynes with good stereocontrol, which also represents a potential route for the asymmetric activation of three continuous inert C(sp³)–H bonds. Gram-scale test and downstream transformations highlight the reliability and practical value of the concept. Mechanistic studies including calculations uncover a featured 1,3-diene formation-driven allylic C(sp³)–C(sp³) bond transposition process, which enables the stereoconvergence of undesired regioisomers from competitive in situ hydrofunctionalization into consistent migration products.

Metal walking is a well-established strategy to enable remote alkene C–H functionalization, yet alkyne walking and remote alkyne hydrofunctionalization remain underdeveloped. Here, the authors report migratory hydroalkylation and hydroamination of alkynes, achieving stereocontrolled asymmetric activation of three consecutive C(sp3)–H bonds.

Introduction

Chain walking is a powerful strategy to enable remote functionalization of the inert alkyl C–H bond^1–10. In particular, transition metal-catalyzed asymmetric chain walking provides efficient routes to access a series of privileged chiral skeletons that are difficult to construct by available methods. Typically, chain walking focuses on the migration of the alkene unit (Fig. 1A, left)^11–56. One reason is that the formed alkyl metal intermediate via alkene metalation is thermodynamically unstable and would undergo facile β-H elimination and reinsertion. With this iterative process, the alkyl metal species can easily migrate to the expected stable position or undergo irreversible transformation, thus driving the reaction forward. The other reason is that unstable alkyl metal species can hardly undergo substitution or coupling with additional reactants as side reactions, due to a more competitive β-H elimination process. Different from the renaissance of alkene migration, alkyne, as another type of feedstock chemical, has never been considered for remote functionalization via metal walking (Fig. 1A, right). The biggest challenge involved is that the in situ formed allyl metal species from alkyne is thermodynamically stable and will easily undergo direct coupling or substitution with additional reactants instead of the expected migration. Thus, migratory functionalization of alkynes is still unknown, which undoubtedly represents an unexplored research field. The related pattern, catalytic reaction, product feature, potential application, and mechanistic character are all elusive.

Fig. 1. The background and our design.

A Migratory functionalization of unsaturated bonds. B Hydrofunctionalization of alkyne. C This design: migratory alkyne functionalization. Nu nucleophile, Ar aryl.

Previously, several cases described migration of conjugated diene and alkyne, but without functionalization^57–63. For example, Hilt, Diver, and Lu reported elegant works on conjugated diene migration to generate other dienes^58–61. In particular, Lu showed that terminal 1,3-diene was isomerized efficiently to a remote site to form aryl-conjugated diene under a Co catalyst⁶¹. Although alkyne isomerization to conjugated diene is known^62,63, until recently, Mazet described a protocol for Pd-catalyzed alkyne migration along an alkyl chain to generate unsaturated ketones with generally low to moderate regioselectivity⁶⁴. In this case, the irreversible formation of the carbonyl unit drives the reaction. However, for all these prior cases, no additional reactants were adopted for further functionalization, due to the unavoidable formation of side regioisomers during migration. Therefore, alkyne migratory functionalization is beyond the present synthetic consideration.

On the other hand, asymmetric hydrofunctionalization of alkynes^65–89 has emerged as a valuable route to construct stereocenters but is limited to in situ transformation (Fig. 1B, left). In contrast, no remote protocol is explored. In 2023, our study unveiled that the alkyne substrate actually underwent the formation of a 1,3-diene intermediate during asymmetric hydrofunctionalization^84,89,90. Based on this important mechanistic discovery and our continuous efforts in asymmetric hydrofunctionalization of unsaturated bonds^{26–28,78,84,87–94}, we hypothesized that if the alkyne unit could isomerize to diene and then keep undergoing iterative β-H elimination and reinsertion before the final allylation, the migratory alkyne functionalization would be possible (Fig. 1C). However, this design faces several formidable challenges. As both allene and diene would form, direct hydrofunctionalization of these intermediates was a more competitive process and would generate undesired regioisomers, especially considering the iterative formation of diene species during migration. Moreover, simultaneous regio- and enantiocontrol along a flexible linear chain made the design more elusive. In particular, once an undesired regioisomer was formed from a carbon nucleophile, the route to convert them into the expected migration product seemed impossible, due to the known inertness of the allyl C–C bond.

Here, we report the proof-of-concept study on migratory alkyne functionalization, which presumably opens an unexplored research field via metal walking. Three different types of alkynes are adopted to undergo remote hydroalkylation and hydroamination through alkyne walking in moderate to high yields and with good regio- or enantioselectivities, corroborating the reliability of the concept. Mechanistic studies show that a featured 1,3-diene formation-driven allylic C(sp³)–C(sp³) bond cleavage and transposition process dominates the conversion of unavoidable regioisomers into desired products and thus guarantees the high regiocontrol of the design.

Results and discussion

Reaction development

We initiated this study by using alkyne 1a bearing a tert-butyl ester and phenylpropyl unit and nucleophile 2a as substrates, Et₃N as both the base and solvent at 80 °C under Pd catalysis. We guessed that the steric hindrance of tert-butyl ester and the obvious electronic difference of ester and aryl groups in the substrate 1a might facilitate the metal-walking process. A series of ferrocene-supported chiral ligands was evaluated first (Fig. 2). When L1 was used, the expected asymmetric alkyne migration occurred, but in low regio- and enantiocontrol (entry 1). L2, as the ligand, only afforded the regioisomer via in situ substitution (entry 2). Other ligands (L3–L7, L9–L14) furnished product 3a in similarly low stereoselectivity or reactivity (entries 3–7, 9, see Supplementary Information Table S1 for details). When L8 was adopted, fortunately, product 3a was observed with a promising result (64% yield, 11:1 rr, 94:6 er). To further improve the stereocontrol, different solvents and additives were evaluated, but all caused the erosion of reactivity and stereoselectivity (entries 10–12, see Supplementary Information Table S2 for more details). However, mixed solvents seemed favorable to the transformation (entries 13–16). When the Et₃N/PhEt combination was selected as mixed solvent at 70 °C for 30 h, the alkyne migration product 3a was isolated in an optimal 79% yield with 18:1 rr and 95:5 er (entry 16).

Fig. 2. Reaction development for migratory alkyne functionalization.

^aThe yield and rr were determined by ¹H NMR (nuclear magnetic resonance). The er was determined by HPLC (high-performance liquid chromatography) analysis. ^bEt₃N (3 equiv) was adopted. ^c2a (1.4 equiv) for 24 h was used. ^d2a (2 equiv) for 30 h at 70 ^oC was adopted. ^eIsolated yield. NaBAr^F₄, Ar^F = 3,5-(CF₃)₂Ph. MTBE methyl tert-butyl ether, n.d. not detected, er enantiomeric ratio, rr regioisomeric ratio. ^tBu, tert-butyl, Cy cyclohexyl.

Scope of alkynes for migratory alkylation

With optimized conditions, the scope of alkynes for asymmetric alkyne migration was evaluated and the results are summarized in Fig. 3A. Aryl-derived alkynes featuring diverse electronic and steric characters showed good compatibility with the transformation (3a–3i). For example, substituents including ether, thioether, phenyl, F, OCF₃, alkyl, and CF₃ units in substrate 1 underwent the stereoselective migration smoothly, affording corresponding products 3a–3i in generally >60% yield, >10:1 rr and 93:7–96:4 er. Large ring and heteroaryl-contained alkynes were also suitable substrates for the reaction (3j–3l). When alkyne 1m substituted by two different esters, was used, a stereoselective alkyne migration with this substrate still occurred, affording corresponding product 3m in moderate yield and selectivities, highlighting the power of the method (Fig. 3B). The bulky character of the tert-butyl ester unit in the substrate 1 m might drive the migration to the less bulky site. In addition, dialkyl-substituted internal alkyne 1n and 1o underwent the migration readily, generating corresponding 3n and 3o in reasonable yields and stereoselectivities (Fig. 3C). In contrast, only in situ hydrofunctionalization process was observed with such propynes as substrates in prior studies.^65–68 It should be noted that when alkyne substrate bearing an internal substituent or with a longer alkyl chain inside, the migratory functionalization process would become very difficult (see Supplementary Information table S4 for details). Based on the present results, it seemed that metal catalyst preferred to migrate to the less bulky site with the formation of a more stable allyl metal species.

Fig. 3. Scope for migratory alkyne functionalization.

A Scope of alkynes. B Diester-substituted alkyne as substrates. C Aryl alkyl-substituted alkynes as substrates. D Scope malonate nucleophiles. E Azole as nucleophiles. The reaction was carried out with 1 (0.1 mmol), 2 (0.2 mmol), [Pd(allyl)Cl]₂ (5 mol%), L8 (10 mol%), NaBAr^F₄ (10 mol%), Et₃N/PhEt (3/1) as mixed solvent at 70 °C for 30 h. Isolated yield. The er was determined by HPLC analysis. The rr ratios were determined by ¹H NMR analysis. ^aAt 80 °C for 24 h. ^b2 (1.5 equiv) was used. ^cYield for the isolated pure major isomer.

Scope of malonates and azoles for migratory alkylation

The scope of different malonates and azoles as nucleophiles was next checked. Different substituents in the malonates, including OTBS, oxetane, F, cyclopentane, and aryl units, reacted with alkyne 1a smoothly, providing 4a–4 f in good yields and stereoselectivities (Fig. 3D). When this protocol was extended to using N-based nucleophiles for the migratory alkyne functionalization, the reactions occurred readily, affording 6a–6c in moderate yields with good regioselectivities, while the corresponding enantioselectivities were unable to control (Fig. 3E). Nevertheless, these cases still represent the undeveloped migratory alkyne hydroamination.

Gram-scale test and downstream transformations

To highlight the reliability of the protocol, a gram-scale test was conducted by using 4 mmol of 1a, and 1.35 g of 3a was prepared in in 83% yield with 9:1 rr and 96:4 er (Fig. 4A). Next, a series of downstream transformations were carried out to showcase the practical value of the method. With sequential ozonization, reduction, transesterification, and decarboxylation, compound 8 was prepared smoothly in retained 96:4 er, which was a precursor to the synthesis of bioactive molecule 11-deoxy PGE₂ (9).^95–97 In addition, an enantioenriched polysubstituted cyclopentane skeleton 13 was readily synthesized from 3a through hydrolysis/selective reduction/cyclization process.

Fig. 4. Transformations and mechanistic studies.

A Gram-scale test and transformations. B Deuterium-labeling experiments. C Intermediate detection. D Convergence tests. E Reaction profile. F Proposed mechanism.

Mechanistic studies

To elucidate the catalytic route of the designed alkyne migration, a set of mechanistic experiments was conducted. First, when deuterated 2a was used to react with 1a, product 3a-d was observed with deuteration at the whole linear carbon skeleton (Fig. 4B). This result was consistent with the character of a palladium hydride-involved process. By quenching the reaction at 9 h, 3a was detected in 28% yield with a surprising 1.8:1 rr. At the same time, conjugated dienes 14 and 15 were detected in 4% and 20% yield, respectively (Fig. 4C, top). These results suggested the conversion of the alkyne substrate into the diene intermediate during the reaction. Meanwhile, the observed low regioselectivity was quite different from the final high regioselectivity for product 3a, which suggested an unexpected catalytic route involving the conversion of regioisomer 3a’ into desired 3a. By using a steric carbon nucleophile 16, no product was obtained, but with the detection of 1,3-dienes 14 and 15, corroborating the proposed diene intermediate formation during the transformation (Fig. 4C, bottom).

To figure out how the initial low regioselectivity was improved to reach a high level finally, regioisomers 3a and 3a’ in 1.3:1 ratio were adopted as substrates under standard conditions (Fig. 4D). In this case, 3a was finally obtained in 99% yield and with a high 14:1 rr. Similarly, with rac-3a’ as the substrate under standard conditions, product 3a was finally observed in 57% yield with 95:5 er, along with 3a’ recovered in 40% yield. These facts clearly suggested that 3a’ would be efficiently transformed into 3a. Based on our group’s prior findings in asymmetric allylic C–C bond functionalization,^98–100. We proposed that an allylic C–C activation might occur to transform 3a’ into diene intermediate 14, which then underwent migration and hydrofunctionalization to form expected product 3a. However, such a proposed C–C activation promoted metal walking has never been reported.

To further shed light on the mechanism, the reaction profile of 3a was described in Fig. 4E. The yield of 3a increased along with reaction time. In this case, the corresponding regioselectivity (3a:3a’) increased from an initial 1:1.3 to a final 15:1, while the enantioselectivity of 3a changed little. This trend further supported the stereoconvergence proposal aforementioned involving the conversion of 3a’ to 3a through C–C cleavage and transposition.

Based on these experiments, a postulated mechanistic route was described in Fig. 4F. Alkyne 3a was first transformed into allene int-2 and then to allyl Pd species int-1. At this point, it might receive nucleophilic attack to generate regioisomer 3a’ or undergo β-H elimination to form conjugated diene intermediate 14. Based on the initially observed low regioselectivity, both two processes existed and might share comparable reactivity. However, regioisomer 3a’ could reform int-1 via allylic C–C activation process and then afford 14. Next, diene 14 would continue to migrate to generate 15. An enantioselective hydrofunctionalization of 15 would finally occur and afford product 3a and regenerate Pd(0) catalyst.

Calculation studies

In order to further support the allylic C(sp³)–C(sp³) bond cleavage and transposition process for stereoconvergence, density functional theory (DFT) calculations were undertaken to elucidate the transformation details from 3a’ to 3a (Fig. 5, see Source Data for more details). The calculations predicted a C–C activation process from regioisomer 3a’-Pd to int-1 with an energy barrier of 27.6 kcal/mol, and identified it as the rate-determining step. From int-1, the pathway proceeded via β-H elimination (ΔG^‡ = 24.2 kcal/mol) to generate the conjugated diene intermediate 14-Pd, which could undergo a thermodynamically favorable migration to give intermediate 15-Pd as a lower-energy conjugated diene intermediate. Following hydrometallation, 15-Pd was further converted into int-3, which then underwent nucleophilic attack via TS-4 (ΔG^‡ = 23.5 kcal/mol) to yield 3a-Pd. Notably, the reverse transformation from 3a-Pd to 3a’-Pd has an overall energy barrier of 31.8 kcal/mol, indicating a kinetically unfavorable pathway to regenerate 3a’-Pd under standard conditions. DFT calculations provide a theoretical foundation for the C–C transposition pathway, with results consistent with experiments and mechanistic proposals.

Fig. 5. DFT Calculation on allylic C(sp³)–C(sp³) bond cleavage and transposition process.

The calculations were performed using the SMD(EthylBenzene)-PBE0-D3-BJ/[6-311++G(d,p)+SDD(Fe&Pd)]//PBE0-D3-BJ/[6-31 G(d,p)+SDD(Fe&Pd)] method.

In conclusion, a concept of migratory alkyne functionalization is described, different from prior broad metal walking studies limited to using alkenes. Three types of alkynes and two types of nucleophiles undergo the migratory functionalization smoothly, enabling remote activation of three continuous inert alkyl C–H bonds simultaneously in good stereocontrol. Gram-scale test and downstream derivatizations highlight the reliability and value of the method. Mechanistic experiments and DFT calculations unveil a mechanistic feature involving 1,3-diene formation-driven stereoselective C(sp³)–C(sp³) bond cleavage and transposition, which guarantees the stereoconvergence for alkyne migration. This proof-of-concept work is expected to open up an unexplored research field for alkyne walking and should be valuable, especially considering that alkynes are feedstock chemicals.

Methods

General procedure for alkyne migratory functionalization

In a N₂-filled glovebox, [Pd(allyl)Cl]₂ (0.9 mg, 0.0025 mmol), L8 (2.8 mg, 0.0050 mmol), sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr^F₄, 4.4 mg, 0.0050 mmol), Et₃N (0.15 mL) and PhEt (0.050 mL) were added sequentially to a 4 mL vial. The resulting yellow solution was allowed to stir at ambient temperature for 1 min. Then alkyne 1 (0.10 mmol) and nucleophiles 2 (0.20 mmol) were added sequentially to the reaction. The reaction mixture continued to stir at 70 °C for 30 h. After this time, the reaction solution will turn yellow to deep red. Then, the reaction was condensed and purified by flash silica gel chromatography to give the pure product 3 or 4.

Author contributions

Z.-T.H. conceived the project. M.-Q.T., X.-X.C., J.-J.Q., and Y.-M.M. performed the experiments. H.-R.X., L.W., and X.-S.X. conducted the computations. Z.-T.H. and X.-S.X. wrote the manuscript with the feedback from all authors.

Peer review

Peer review information

Nature Communications thanks Shaolin Zhu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Data availability

Data supporting the findings of this manuscript are also available from the corresponding author upon request. The coordinates of the optimized structures in this study are provided in the Source Data. For experimental details and procedures, spectra for all unknown compounds, see Supplementary Information file. Source data are provided with this paper.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-026-72695-z.