Nickel-catalyzed diastereoselective hydroboration of acrylates with a vinylborane reagent

Abstract

Organoboron compounds exhibit unique properties and valuable applications in organic synthesis, catalysis, materials science, and drug discovery, driving researchers to improve their structural and functional diversity. Despite significant advancements, challenges remain in accessing complex organoboron compounds, particularly in constructing boron-stereogenic skeletons. Here we report a nickel catalyzed diastereoselective hydroboration of olefins using a newly developed vinylborane reagent, CH₂=CH–BH₂L (where L is a dative donor). This protocol enables the efficient synthesis of versatile vinylborane derivatives featuring a boron-stereogenic center. Mechanistic studies, including the isolation and structural characterization of a key B–H–Ni bonded intermediate, control experiments, and DFT calculations reveal a σ-coordination enabled B(sp³)–H activation. The σ-coordination induces an oxidative metalation, simultaneously forming B–Ni, C–Ni and C–H bonds. The C=C unit in the vinylborane reagent plays a pivotal role in facilitating the otherwise challenging oxidative metalation of the B(sp³)–H bond. This unique B(sp³)–H metalation mode may have broader implications for achieving other forms of selective B–H functionalization.

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Introduction

Organoboron compounds are finding increasingly valuable applications in synthetic chemistry, materials science, and drug discovery. Notably, due to the unique interactions between borane motifs and bioactive centers, five boron-based drugs have been approved by the FDA, and more candidates are under clinical trials (Fig. 1a).^1–3 Furthermore, boron-containing units such as azaborines^4–6 and carboranes^7,8 serve as benzene analogues to enhance or alter the bioactivity of the lead drug molecules. Given these advancements, it remains a compelling goal to enhance the structural and functional complexity of organoboron molecules. Despite significant progress, challenges persist in the synthesis of complex organoboranes, particularly in constructing boron-stereogenic skeletons.^9,10 To address these challenges and expand the chemical space of organoboranes, design and development of a versatile reagent would be an ideal solution.

Fig. 1 Vinylborane reagent. (a) Unique interactions between boron motifs and biomolecules, and representative FDA-approved boron drugs. (b) Representative reaction modes of vinylboron reagents and the unexplored B(sp³)–H functionalization. (c) This work: design of a vinylborane reagent and its reaction with olefins via nickel catalysis.

In view of the inherent versatility of C=C and C–B units, vinylboron reagents containing both active centers have been developed and proven to be powerful synthons for organoborane synthesis and organic transformations (Fig. 1b).^11–19 These reagents typically undergo three main reaction modes, including (1) C=C double bond modifications,^20–30 (2) C–B bond transformations,^13,31–34 and (3) 1,2-migrations of “boron-ate” complexes.^35–39 However, functionalization at the boron center assisted by the C=C motif in vinylboron reagents remains unexplored, despite its potential to access boron-stereogenic compounds. In this connection, we have designed a bench-stable vinylborane reagent, CH₂=CH–BH₂L (1, L is a dative donor). This reagent is hypothesized to undergo B(sp³)–H functionalization to generate a broad range of vinylborane derivatives distinguished by a chiral-at-boron center (Fig. 1b).^9,10,40–44 For realizing effective B(sp³)–H modification, the activation strategy should be able to differentiate the B(sp³)–H site from other active centers in 1 and allow for precise selectivity control.

A promising approach for selective B–H derivatization involves transition metal catalysis,^45–52 which has been widely applied in borylative transformations^53–65 but remains relatively underdeveloped in B(sp³)–H activation.^66–68 Pioneering studies by Weller,⁶⁹ Chuzel and Parrain,⁴³ and Shi⁷⁰ demonstrated noble metal catalysts (e.g., Rh, Au) for B(sp³)–H functionalization, but successful examples remain scarce. This difficulty arises because B(sp³)–H bonds are electron-rich, weakly polarized, and lack an empty p-orbital on boron, making their oxidative addition on transition metals challenging compared to B(sp²)–H bonds. Interestingly, several studies document σ-coordination of B(sp³)–H bonds to transition metal centers, which weakens the B(sp³)–H bond and may facilitate its activation.^71–75 Building on this premise, we have developed a nickel-catalyzed diastereoselective hydroboration of olefins using the vinylborane reagent (Fig. 1c). The successful isolation and structural characterization of a key B–H–Ni bonded intermediate, along with control experiments and DFT calculations, reveal a unique σ-coordination enabled oxidative metalation that simultaneously generates B–Ni, C–Ni and C–H bonds while cleaving the B–H bond and olefin π bond. The C=C unit in the vinylborane reagent plays a crucial role in facilitating the key oxidative metalation of the B(sp³)–H bond.

Results and discussion

In the presence of NiBr₂(PPh₃)₂ as a catalyst, reaction of the vinylborane reagent 1 with benzyl acrylate in dioxane at room temperature overnight gave the coupling product 3 in 80% yield with a diastereomeric ratio (d_r) of 8 : 1 (entry 1, Table 1). Using NiCl₂ as the catalyst without a phosphine ligand provided a comparable yield of 75%, but with a significantly reduced d_r of 1.1 : 1 (entry 2, Table 1). We then screened a series of ligands to improve the d_r of product 3 (Table 1 and S1b in the ESI†). Mono-phosphine ligands, P(p-F–Ph)₃ and P(p-Cl–Ph)₃, proved optimal, leading to excellent d_rs of > 20 : 1. The most electron-deficient P(C₆F₅)₃, electron-rich PCy₃, or bidentate phosphine ligands offered low d_rs ranging from 1 : 1 to 2 : 1 (entries 7 and 9, Tables 1 and S1b in the ESI†). Using less polar toluene as the solvent increased the yield to 97% without compromising the d_r (entry 12, Table 1). The employment of Ni(COD)₂ instead of NiCl₂ resulted in a decreased yield of 84% with a reduced d_r of 16 : 1 (entry 13, Table 1). Reducing the loadings of NiCl₂ and P(p-F–Ph)₃ to 5 mol% and 12.5 mol%, respectively, did not affect the reaction efficiency (entry 14, Table 1) and was therefore chosen as the optimal reaction condition. Replacing the vinylborane reagent 1 with NHC–BH₃ or NHC–BH₂Ph failed to give the target product (Section 4.4 in the ESI†), highlighting the important role of the “C=C” motif in 1 in facilitating B–H metalation/activation. In contrast, the previously developed boryl radical strategy proved to give β-borylation products with poor diastereoselectivity (Fig. S14†).^66,76–80

Table 1 Synthesis of 1 and optimization of reaction conditions^a

Entry	[Ni] (10 mol%)	PR3 (25 mol%)	Solvent	Yield^b (%)	d r
a Reactions were conducted at 0.05 mmol scale in 0.5 mL of solvent in a closed flask. b Yields and drs were determined by ^1H NMR with 1,3,5-trimethoxybenzene as an internal standard. c 5 mol% NiCl2 and 12.5 mol% P(p-F–Ph)3 were used, isolated yield in parentheses.
1	NiBr2(PPh3)2	—	Dioxane	80	8/1
2	NiCl2	—	Dioxane	75	1.1/1
3	NiCl2	PPh3	Dioxane	88	19/1
4	NiCl2	P(p-F–Ph)3	Dioxane	92	>20/1
5	NiCl2	P(p-Cl–Ph)3	Dioxane	88	>20/1
6	NiCl2	P(p-OMe–Ph)3	Dioxane	89	18/1
7	NiCl2	P(C6F5)3	Dioxane	72	1.1/1
8	NiCl2	P(p-Me–Ph)3	Dioxane	91	12/1
9	NiCl2	PCy3	Dioxane	42	2/1
10	NiCl2	P(p-F–Ph)3	MeCN	37	11/1
11	NiCl2	P(p-F–Ph)3	DMA	87	14/1
12	NiCl2	P(p-F–Ph)3	Toluene	>95	>20/1
13	Ni(COD)2	P(p-F–Ph)3	Toluene	84	16/1
14	NiCl 2	P(p-F–Ph) 3	Toluene	>95 (97)	>20/1

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To gain insights into the reaction mechanism, control experiments were conducted. Treatment of 1, Ni(COD)₂, and P(p-F–Ph)₃ in THF at room temperature for 6 h produced a B–H–Ni bonded complex INT1 in 60% isolated yield (Fig. 2a). The ¹H NMR spectrum of INT1 exhibited a significantly up-field peak at −0.88 ppm (Fig. 2c). Its assignment to one BH was supported by the subsequent ¹¹B–¹H HSQC analysis, with another BH being detected at 0.66 ppm (Fig. 2c). The B(sp³)–H coordination mode was further verified by the single-crystal structure of INT1 (Fig. 2a). Upon hydrogen addition through modeling, the bond length of the B(sp³)–H σ-coordinated to the Ni center was measured as 1.29 Å, longer than the 1.13 Å length measured for the free B(sp³)–H bond. Moreover, the distance between the B and Ni centers was found to be 2.28 Å, suggesting a potential interaction. A combination of the NMR and X-ray diffraction findings indicated (1) the σ-coordination of one B(sp³)–H in the vinylborane reagent to the Ni center and (2) the significant activation of this B(sp³)–H bond by Ni. Such a bonding and activation mode differs from the deprotonation or C–H metalation reaction observed in forming transition metal-allylic complexes,^81,82 probably due to the distinct electronic nature of B(sp³)–H (hydridic) versus C–H (protonic). Compound INT1 reacted with ethyl (E)-2-hexenoate under the standard conditions to deliver 41 in 21% yield with a d_r of over 20 : 1 (Fig. 2b). It was also proved effective as a catalyst in the hydroboration reaction (Fig. 2b). These results support the role of INT1 as a key intermediate involved in the reaction pathway.

Fig. 2 Mechanistic investigations. (a) Synthesis and single crystal structure of INT1. (b) Demonstrating the role of INT1 in catalytic hydroboration. (c) ¹H–¹¹B HMQC spectrum of INT1. (d) Deuterium labelling experiments. (e) KIE determination experiments. (f) Proposed reaction mechanism. (g) DFT calculations on B3LYP-D3(BJ)/def2-QZVPP (Ni), def2-TZVP (rest)/SMD (toluene)//B3LYP-D3(BJ)/def2-TZVP (Ni, P), 6-31G(d,p) (rest)/PCM (toluene) level; relative Gibbs free energies and relative electronic energies (in parentheses) in kcal mol⁻¹.

DFT calculations were carried out to gain insight into the reaction mechanism. Fig. 2g shows the energy profile calculated. Starting from INT1 (using its single crystal structure for geometry optimization), a ligand substitution of benzyl acrylate for P(p-F–Ph)₃ leads to the formation of INT2, from which the crucial oxidative metalation occurs, establishing B–Ni, C–Ni, and C–H bonds in INT3 concurrently, while cleaving a B–H bond and benzyl acrylate π bond. The energy barrier for this metalation step is 19.9 kcal mol⁻¹, being the highest in the calculated pathway (Fig. 2g). Subsequently, INT3 undergoes reductive elimination, followed by product release to deliver the final product and regenerate INT1. Diastereoselectivity control is closely associated with the rate-determining step. Therefore, optimization was conducted for the four diastereomers of TS1, originating from three chiral B, Ni, and C (bonded with the ester group) centers (Fig. S15 in the ESI†). Among them, the diastereomer with the least steric repulsion between the olefin substrate and the phosphine ligand was most favored (Fig. 2g), leading to product 3 with a configuration identical to experimental observations (see single crystal structures of 4 and 21 in Fig. 3).

Fig. 3 Substrate scope. Reaction conditions: NiCl₂ (5 mol%), P(p-F–Ph)₃ (12.5 mol%), 1 (0.12 mmol), alkene (0.1 mmol), PhMe (1 mL), r.t., 16 h; yields of isolated products. (a) ¹H NMR yields are shown in parentheses. (b) Reaction conditions: Ni(COD)₂ (10 mol%), P(p-F–Ph)₃ (25 mol%), 1 (0.12 mmol), alkene (0.1 mmol), PhMe (1 mL), r.t., 16 h.

The deuterated vinylborane reagent 1-D was prepared and reacted with 2-furanone to yield 49-D, wherein one hydrogen of the β-CH₂, with respect to boron, was deuterated at a rate of 67% (Fig. 2d). The addition of 1.5 equiv. of D₂O into the reaction mixture did not cause any B–H or C–H deuteration (Fig. 2d). Competitive and parallel experiments using 1 and 1-D displayed significant kinetic isotope effect (KIE) with k_H/k_D ratios of 2.5 and 2.4, respectively (Fig. 2e). These experimental findings suggested that the B(sp³)–H cleavage might be involved in the rate-determining step, consistent with the computational results. Based on the above experiments and DFT calculations, a plausible reaction pathway is proposed in Fig. 2f.

The reaction mode of B(sp³)–H metalation is very similar to the documented ligand-to-ligand hydrogen transfer (LLHT) mechanism observed in C(sp²)–H nickelation.^83,84 The difference lies in the bond strength between Ni–B(sp³) and Ni–C(sp²). The former one is believed to be relatively weak due to the lack of π-interaction between metal and the boron unit.⁸⁵ Therefore, its formation via LLHT is involved in the rate-determining step.

We then explored the scope of various types of olefins. Terminal vinyl esters containing a diverse array of functional groups, including alkyl, trifluoromethyl, alkenyl, alkynyl, cyano, methoxyl, ether, halide, silyl, carbonyl, amide, ester, bpin, and pyridinyl groups, reacted with the vinylborane reagent smoothly (3–29, Fig. 3). Most reactions exhibited excellent diastereomeric ratios of >20 : 1. Notably, carbonyl and pyridinyl substituents, which can coordinate to nickel, were well tolerated (21 and 29). The hydroboration occurred regioselectively at the relatively electron-poor C=C site, when the substrates involved multiple unsaturated functionalities (10–14). The ferrocene-containing substrate worked well (30), while the cyclobutylamino substituent proved compatible (31). A series of aryl acrylates were evaluated, giving 32–38 in moderate to excellent isolated yields, yet with relatively low diastereomeric ratios of around 10 : 1. Alkyl thioacrylate was also an effective coupling partner, delivering product 39.

A series of internal olefins were subsequently evaluated as substrates. Various functional groups including piperidine, tetrahydropyrane, nerolin, and phthalimide were well tolerated (42–45). The substrate featuring a cyclopropylethene motif underwent this hydroboration effectively to afford 46, where the cyclopropyl ring remained intact, negating the involvement of a radical pathway. In addition to 1,2-disubstituted olefins, the 1,1′-disubstituted one also worked well (50), constructing a quaternary C–B(sp³) bond. Tri-substituted olefins afforded the corresponding products (51, 53–55) effectively, albeit with compromised diastereomeric ratios. However, the tetra-substituted olefin failed to react with the vinylborane reagent 1 (Section 4.4 in the ESI†). These results imply the influence of steric factors on the reaction efficiency and diastereoselectivity. Less bulky cyclic olefins were compatible, yielding 49 and 52 with diastereomeric ratios of >20 : 1.

This protocol also enabled the straightforward introduction of a versatile vinylborane motif into a broad array of bioactive molecules, including derivatives of commercially available medicines (Fig. 4a): diclofenac (61, anti-inflammatory), probenecid (62, for treating gout and hyperuricemia), febuxostat (63, for treating gout), telmisartan (66, for treating high blood pressure, heart failure, and diabetic nephropathy), ciprofibrate (68, a hypolipidemic agent), and indometacin (65 and 67, anti-inflammatory). Additionally, cholesterol (64), estrone (60), Boc-Ser-OMe (59, an amino acid), diacetone-D-glucose (58, a pharmaceutical intermediate), menthol (57, anti-irritation), isoborneol (56, antiviral), and butenolide (69, a marine drug) derivatives reacted well with the vinylborane reagent, achieving good to excellent diastereomeric ratios. These findings highlight the remarkable compatibility and promising potential of this nickel-catalytic protocol.

Fig. 4 Derivatization and synthetic applications. (a) Integrating the vinylborane motif into commercial medicine and natural product derivatives. (b) Large-scale synthesis and downstream transformations of the products.

This nickel-catalyzed hydroboration was conveniently scaled up to give 3 and 50 in 97% and 72% yields, respectively (Fig. 4b). The introduced vinylborane motif is anticipated to be versatile for further molecular modifications, alike the previously reported vinylboron fragments. Treatment of 3 with in situ generated [Fe]–H species^86,87 delivered a new α-boryl(sp³) radical, which effectively attacked olefins or diazo compounds to give 72–74 and 70–71, respectively. The ester groups in 3 and 50 were conveniently reduced to give 75 and 76. Attempts to construct a four-membered oxaboracycle from 76via Brønsted acid catalyzed B–H/O–H dehydrogenative coupling failed. However, an unexpected product 78 was isolated and characterized (see Fig. S3 in the ESI†). A plausible pathway including a sequence of borenium-induced alkenyl metathesis, nucleophilic 1,2-boryl shift, and carbocation hydridation was proposed accordingly (see Fig. 4b and S4 in the ESI†). Reaction of 50 with the diazo compound upon visible light irradiation yielded 77 bearing a bicyclo[3.1.0] ring,⁶² rather than the B–H insertion species.⁵⁸

Conclusions

In summary, we have designed a new vinylborane reagent that permits the facile modification at the boron center via B(sp³)–H bond functionalization. The developed nickel catalytic protocol demonstrates advantages of remarkable diastereoselectivity control, good compatibility, and mild operation conditions. The isolation and structural characterization of a B–H–Ni bonded intermediate, along with DFT calculations, underscore the important bidentate coordination of the vinylborane reagent to the nickel center. This coordination induces a unique oxidative metalation, distinct from the metalation modes observed for allylic C–H bonds. The potential of this vinylborane reagent in synthetic chemistry awaits further research efforts.

Data availability

Crystallographic data for INT1, 4, 21 have been deposited at the CCDC under 2381595, 2381592, 2381593 and can be obtained from https://www.ccdc.cam.ac.uk/. Detailed synthetic procedures, characterization of boranes, and mechanistic investigations supporting this article have been uploaded as ESI.†

Author contributions

G. H., X. W., and Y. Q. conceived and designed the experiments. G. H., P. Z., X. W., C. W., and Y. F. performed experiments. C. W. and W. H. L. performed crystallization and structural resolution. P. Z. and Z. L. performed DFT calculations. G. H., P. Z., Z. L., and Y. Q. wrote the manuscript. Z. L. and Y. Q. directed the research.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors acknowledge the start-up funding (Project No. R9804 to Y. Q.) from the Hong Kong University of Science and Technology (HKUST), Early Career Scheme from the Research Grants Council of Hong Kong (Project Number: 26307123 to Y. Q.), NSFC Young Scholar Fund (Project Number: NSFC23SC02 to Y. Q.), and the General Research Fund from the Research Grants Council of Hong Kong (HKUST 16302222 to Z. L.). Dr Herman Ho-Yung SUNG and Prof. Dr Ian Williams are acknowledged for X-ray crystallography. Dr Yu CAO, Prof. Dr Wan CHAN and Ms. Wing-Laam LUK are acknowledged for HRMS test.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2381595, 2381592 and 2381593. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5sc02695d

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