Cu-catalyzed enantioconvergent deborylative alkynylation

Abstract

Alkylboronic pinacol esters represent a highly attractive class of reagents due to their modular synthesis and unique reactivity conferred by the vacant boron p-orbital. However, their direct application in asymmetric C–C cross-coupling reactions remains underexplored. Herein, we report a Cu-catalyzed deborylative strategy to access α-chiral alkynes that delivers good enantioselectivity and accommodates a broad range of functional groups and heterocycles. The reaction is proposed to proceed through a radical-relay pathway: an aminyl radical-mediated C–B bond cleavage followed by Cu-catalyzed asymmetric alkynylation. The reaction mechanism was probed using a combination of radical clock ring-opening study, radical trapping experiments, and enantioconvergence test with enantioenriched starting materials. Density functional theory (DFT) calculations demonstrate the feasibility of a Cu-mediated inner-sphere C–C bond-forming pathway and attribute the observed enantioselectivity to attractive ligand-substrate halogen-π interactions.

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Introduction

Alkylboronic pinacol esters have emerged as highly versatile reagents in organic synthesis.^1–5 Their capacity for iterative homologation through 1,2-boronate rearrangement allows for efficient and stereocontrolled assembly of complex frameworks.^6–9 The unique stability and reactivity of α-borylcarbanions render them readily accessible intermediates for alkyl skeleton construction.^10–15 Despite their synthetic potentials imparted by the vacant boron p orbital, the application of alkylboronic pinacol esters in asymmetric deborylative C–C cross-coupling remains limited due to sluggish transmetalation and competing protodeboronation pathways.¹⁶ In particular, an enantioconvergent deborylative alkynylation protocol could unlock powerful synthetic disconnections by combining the modularity of alkylboronic pinacol esters and versatility of alkynyl groups (Fig. 1A)—yet such a transformation remains elusive. Seminal work by Aggarwal¹⁷ and Morken¹⁸ (Fig. 1B) demonstrated the potential of enantioenriched alkylboronic pinacol esters for α-chiral alkyne synthesis via (1) enantiospecific Zweifel-type alkenylations followed by 1,2-elimination, and (2) stereoretentive transmetalation to CuCN facilitated by alkyl lithium reagents and subsequent coupling with alkynyl bromides, respectively. We reasoned that an alternative enantioconvergent strategy, which directly engages racemic alkylboronic pinacol esters with readily available terminal alkynes, could provide a streamlined approach to these valuable products. We herein disclose the first enantioconvergent deborylative alkynylation protocol facilitated by ligand design and proceeding through a Cu-catalyzed radical relay.^19–21

Fig. 1 (A) A Cu-catalyzed asymmetric deborylative cross-coupling approach to α-chiral alkyne synthesis; (B) stereospecific transformations as the only examples of deborylative protocols to access α-chiral alkynes; (C) employing alkylboronic pinacol esters in enantioconvergent alkynylation through single-electron processes.

We envisioned that this transformation could be achieved through two key mechanistic steps (Fig. 1C): (1) the homolytic cleavage of C–B bonds and (2) the asymmetric functionalization of alkyl radicals via Cu(II) alkynyl intermediates.^22–31 The single-electron activation of alkylboronic pinacol esters is often hindered by their high oxidation potential.^32–34 We previously overcame this challenge by employing an in situ generated aminyl radical to promote C–B bond homolysis through an inner-sphere pathway.^34–36 Following the C–B bond activation (steps a–b), we propose that the resulting prochiral radical engages an in situ generated Cu(II) bisalkynyl intermediate, yielding the optically active product (steps c and d). We anticipate that potential complications with this approach involve (1) homocoupling of terminal alkynes and (2) undesired C–N coupling with amine activator. We further reasoned that these challenges could be circumvented through the judicious choice of base additives and oxidants to balance the relative rates among alkyne transmetalation, C–B bond activation, and radical functionalization steps. We herein report the successful implementation of this strategy for an enantioconvergent deborylative alkynylation protocol and the corresponding mechanistic studies to guide our future expansion of this C–C cross-coupling platform.

Results and discussion

Reaction optimization

We initiated our investigation by examining the cross-coupling between alkylboronic pinacol ester 1a and 2-ethynylthiophene 2a. We tested a range of copper sources, chemical oxidants, amine additives, external bases, and reaction solvents (See SI, Table S1 for full optimization details). The focus on inda(box)-type ligands (box: bisoxazoline) was motivated by the pioneering work of Liu et al.,^20–23 who demonstrated their utility in asymmetric radical alkynylation. A combination of cuprous trifluoromethanesulfonate benzene complex and parent inda(box) ligand L1 yielded product 3a with moderate yield and enantioselectivity (Table 1). We identified two potential strategies to improve the reaction selectivity: (1) tuning the ligand bite-angle via meso-substitution³⁷ and (2) enhancing ligand-substrate interactions by installing distal substituents.^38–40 While introducing methyl (L2–L3) or other groups (Table S1) to the meso-position diminished the reaction yield,⁴¹ modifications at the phenyl meta-position (L4–L6) proved effective. In particular, bromine substitution in L6 delivered the highest yield and enantioselectivity. We attributed this observation to ligand-substrate halogen-π interactions^40,42,43 within the C–C bond-forming transition structures as indicated by DFT calculations (vide infra).

Table 1 Reaction Optimisation^a

Entry	Variation from standard conditions	Yield (%)	Er
a Reaction conditions unless otherwise noted: 4,4,5,5-tetramethyl-2-(1-phenylhexyl)-1,3,2-dioxaborolane (1a, 0.10 mmol), 2-ethynylthiophene (2a, 0.30 mmol), aniline (0.10 mmol), specified catalyst mixture, di-tert-butyl peroxide (0.30 mmol), and toluene (0.1 M); reaction yields were determined by ^1H NMR spectroscopy of the crude reaction mixture using 1,1,2,2-tetrachloroethane as an internal standard (see the SI for details). The enantiomeric ratio (er) of product 3a was determined by chiral high-performance liquid chromatography (HPLC) analysis.
1	None	83	91 : 9
2	CuI as copper source	46	90 : 10
3	Cu(CH3CN)4PF6 as copper source	44	88 : 12
4	(cumylO)2 as oxidant	38	90 : 10
5	PhI(OAc)2 as oxidant	0	—
6	^tBuOOH as oxidant	0	—
7	DCM as solvent	56	88 : 12
8	PhCl as solvent	66	89 : 11
9	DMAP as additive	<5	—
10	4-Trifluoromethylaniline as additive	<5	—
11	4-Methoxyaniline as additive	70	90 : 10
12	No additive	0	—
13	23 °C	12	91 : 9
14	80 °C	58	89 : 11
Ligand optimization:

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Among the oxidants tested, feedstock chemical di-tert-butyl peroxide (^tBuO)₂ provided the highest yield of 3a while minimizing alkyne homocoupling compared to other oxidants commonly employed in cross-coupling reactions (entries 4–6, see also Table S2).^19–21 We anticipate that the amine additive is crucial in facilitating the single-electron activation of alkylboron reagents.^34–36 A range of substituted anilines and alkylamines were tested, with the highest yield and enantioselectivity obtained using a stoichiometric amount of aniline (entries 9–12, see also Table S2). No C–N coupling was observed under the optimized reaction conditions. Reaction carried out in toluene (entries 7–8, Table S2) at 60 °C (entries 13–14) yielded the optimal result. An exogenous base was employed to promote the alkyne transmetalation step, with the best outcome achieved using Cs₂CO₃ (Table S2).

Substrate scope

With the optimized reaction conditions, we assessed the functional group tolerance and scope of compatible alkylboronic pinacol esters and alkynes (Fig. 2). The absolute configuration of the major enantiomer was determined by a combination of optical rotation measurements and the solid-state structures of products 3c and 3l. The reaction proceeds effectively in the presence of various heterocycles commonly found in pharmaceuticals,^44–47 including thiophene (3a), pyrrole (3b, 3l), benzoxazole (3e), pyrazole (3h), indole (3j), benzothiazole (3k, 3r), indazole (3m), isoquinoline (3o), thiochromane (3t), and pyridine (3u).

Fig. 2 Reaction Scopea (a) all yields were obtained using 0.50 mmol of alkylboronic pinacol ester substrates unless otherwise noted. Enantiomeric ratio (er) was determined by chiral HPLC analysis. (b) Reaction carried out on a 5.00 mmol scale of substrate 1a. (c) Solid-state molecular structure of 3c and 3l with thermal ellipsoids at 50% probability level. Colour scheme: S, yellow; N, blue; C, grey, O, red, F, yellow-green, H, white.

Functionalization of substrates containing aza-heterocycles (3h, 3m, 3o, 3q, 3r) proceeds effectively with no detectable side products resulting from radical addition. Functional groups prone to oxidation, such as thioether (3t), are tolerated under reaction conditions. The protocol is compatible with weak allylic (3g)/benzylic C–H bonds (3c, 3f) and proceeds smoothly in the presence of alkyl halide (3i). These results highlight the orthogonality of the deborylative alkynylation approach to emerging catalytic strategies, such as asymmetric C–H functionalization or Sonogashira-type transformations.^22–30 The protocol exhibits high selectivity between different alkylboronic pinacol esters. For substrates containing additional aryl (3f) or primary alkyl boronic esters (3d), only the products resulting from benzylic functionalization were obtained. To further highlight the synthetic utility of the enantioconvergent alkynylation protocol, the synthesis of 3a was carried out on a 5.0 mmol scale, resulting in comparable yield and enantioselectivity to the 0.5 mmol scale reactions.

Mechanistic investigation

Building on the successful application of the alkynylation protocol across a broad substrate scope, we integrated experimental and theoretical studies to elucidate the reaction mechanism and origin of enantioselectivity, with the goal of guiding future chiral ligand design and advancing the asymmetric deborylative C–C cross-coupling platform. Alkynylation of radical clock substrate 4 led to the formation of product 5a and ring-opened 5b, indicating the intermediacy of an alkyl radical (Fig. 3A). Radical trapping experiments were carried out using TEMPO and CBrCl₃ (Fig. 3B). In both cases, the formation of 3n was inhibited while the TEMPO-coupled product 6 and brominated product 7 were observed in 32% and 26% yield, respectively, supporting the involvement of an alkyl radical intermediate. Subjecting enantiomerically enriched R- or S-1n to the reaction conditions resulted in the generation of product 3n with a similar enantiomeric ratio favoring the same major enantiomer, indicating the loss of stereochemical information prior to C–C bond formation (Fig. 3C).

Fig. 3 Mechanistic probes for the asymmetric deborylative alkynylation (reactions were carried out on a 0.10 mmol scale. Yields were determined by ¹H NMR spectroscopy of the crude product mixture using 1,1,2,2-tetrachloroethane as an internal standard). (A) The proposed alkyl radical formation is supported by radical ring opening of the cyclopropyl substituent in substrate 4. (B) The alkyl radical intermediates can be intercepted using radical traps. (C) Stereochemical information is lost after the generation of an alkyl radical.

Computational studies were next carried out to investigate our proposed mechanism and elucidate the origins of enantioconvergence. Dispersion-corrected DFT calculations were performed at the B3LYP-D3(BJ)/def2-TZVP-SMD(toluene)//B3LYP-D3(BJ)/def2-SVP & def2-TZVP(Cu, Br)-SMD(toluene) level of theory.^48–54 We modelled the coupling between alkylboronic pinacol ester 1n and 2-ethynylthiophene 2a with ligand L6via an inner-sphere pathway.²² Our previous computational study³⁵ indicated that among several plausible C–B bond activation pathways, inner-sphere aminyl radical activation is kinetically most favourable. We propose that an analogous mechanistic framework underlies the alkynylation system. Control experiments (Table 1, entries 10–12) underscore the critical role of aniline in this protocol. We hypothesized that substrate 1n undergoes aminyl-radical-mediated C–B bond cleavage: H-atom transfer between aniline and tert-butoxy radical generates the anilinyl radical (Fig. 1C), which in turn initiates C–B bond homolysis in 1n to produce alkyl radical 9·and ArNH–Bpin as a stoichiometric byproduct. (see SI, Scheme S1 and S2 for details).³⁵ Computational results (Fig. 4A) indicated that the addition of radical 9 to divalent Cu intermediates 8 ⁵⁵ is slightly endergonic, generating formal Cu(III) intermediates 10_R. (ΔG = 1.7 kcal mol⁻¹) and 10_S (ΔG = 1.5 kcal mol⁻¹). The subsequent C–C bond formation proceeds via competing diastereomeric reductive elimination transition structures (TSs) TS1_R and TS1_S, with retention of configurations at the benzylic positions. While formation of 10_s is slightly favoured thermodynamically (ΔΔG = 0.2 kcal mol⁻¹), the R-enantiomer pathway is kinetically preferred (ΔΔG^‡ = 0.7 kcal mol⁻¹, consistent with experimental observations), indicating that radical 9 capture is likely reversible and proceeds with a low barrier. Analysing the noncovalent interaction (NCI) isosurfaces of TS1_R and TS1_s attributes the selectivity to attractive ligand-substrate halogen–π interactions^40,42,43 between a bromine substituent and an axial 2-thiopheneacetylide ligand (Fig. 4B). The bond metrics (Br–Ar(centroid) distance: 3.61 Å; C–Br–Ar(centroid) angle: 104.4°)⁵⁶ are consistent with halogen–π interactions observed in enzymatic systems, where aromatic side chains align to facilitate arene electron density donation to the σ-hole of the C–Br bond.^42,57 Similar interaction is absent in TS1_S due to the opposing orientation of ligand Br substituent and the alkynyl group (Scheme S7).⁵⁸

Fig. 4 Computational investigation into the C–C bond-forming mechanism. (A) Potential energy surface of alkynylation via an inner-sphere pathway. (B) Reductive elimination transition state structures reveal favourable non-covalent halogen–π interaction in TS1_R. (B3LYP-D3(BJ)/def2-TZVP-SMD(toluene)//B3LYP-D3(BJ)/def2-SVP-SMD(toluene)). Alkyl fragment is coloured green. The forming C–C bond is coloured red.

Conclusions

In summary, we have developed a Cu-catalyzed enantioconvergent deborylative alkynylation protocol. This method is compatible with a wide range of functional groups and heterocycles. The alkynylation product can be obtained on a gram scale with good enantioselectivity. Mechanistic evidence suggests the generation of prochiral radicals in a stereoablative fashion, followed by enantioselective radical trapping by Cu(II) intermediates. DFT calculation supports the viability of an inner-sphere mechanism and attributes the observed enantioselectivity to ligand-substrate halogen–π interactions.

Author contributions

YD conceptualized the work. JFH, YD, and BZ performed the experiments in this project. TJS carried out the computational work. YD, JFH, and TJS prepared the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2446256 and 2446257 contain the supplementary crystallographic data for this paper.^59a,b

All experimental procedures and data related to this study can be found in the SI. Supplementary information is available. See DOI: https://doi.org/10.1039/d5sc04733a.

Acknowledgements

This work was supported by startup funds from Colorado State University. We are grateful to Dr Robert S. Paton for advice on the computational study in this manuscript.

Notes and references

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