Nickel‐Catalyzed Boron‐Mediated Saturative Trifunctionalization of Alkynes

ABSTRACT

Converting simple alkynes into fully substituted alkanes—installing three distinct groups via a sequential one‑pot process—remains a formidable challenge. Herein, we report a boron‐mediated, nickel‐catalyzed strategy that achieves this transformation, enabling the modular assembly of valuable 1,1‐diarylalkanes from both simple alkynyl tetracoordinate borons and N‐acylglutarimides. The reaction proceeds with high regio‐ and chemoselectivity under mild conditions, exhibiting good functional group tolerance across both coupling partners. Mechanistic studies support a unique reaction pathway involving dual 1,2‐metallate shifts, with water serving as the terminal proton source. The synthetic utility is demonstrated through one‐pot synthesis, late‐stage functionalization of drugs, gram‐scale reactions, and versatile downstream transformations of the products. This strategy represents a distinct strategy that differs from stepwise alkyne reduction, offering a useful disconnection for complex alkane synthesis starting from alkynyl tetracoordinate borons or terminal alkynes via one‑pot borylation.

A Ni‐catalyzed boron‐mediated saturative trifunctionalization of alkynes is developed, enabling one‐step installation of three distinct groups via dual 1,2‐metallate migrations to access fully substituted 1,1‐diarylalkanes. Featuring an inexpensive catalyst, good compatibility, high efficiency, and exceptional selectivity, its utility is demonstrated through one‐pot synthesis, late‐stage drug modifications, and gram‐scale reactions. This strategy offers a route shift toward programmable alkane synthesis.

1. Introduction

Alkyne functionalization has long been a central theme in modern synthetic organic chemistry [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. The unique linear geometry and orthogonal π‐system of the carbon‐carbon triple bond render alkynes exceptionally versatile building blocks, enabling access to complex architectures found in natural products, pharmaceuticals, and functional materials [11, 12, 13, 14, 15, 16]. Among the developed diverse transformations, the difunctionalization of alkynes—the simultaneous addition of two distinct functional groups across the triple bond—has matured into an effective strategy for the stereoselective and regioselective synthesis of tri‐ or tetrasubstituted alkenes (Figure 1a, left). These multi‐substituted olefins are pivotal structural motifs in biologically active compounds and important intermediates in materials science [17, 18, 19, 20, 21]. Over the years, a vast array of catalytic systems involving transition metals such as palladium, rhodium, and copper have been established to achieve carbon‐heteroatom and carbon‐carbon difunctionalization with high fidelity [17]. However, a more formidable challenge lies in the direct, multicomponent saturation of alkynes into fully substituted alkanes. While the conversion of an alkyne to an alkane via sequential or stepwise processes is well‐documented, a single catalytic operation that installs three distinct functional groups onto a saturated carbon framework represents a distinctly more complex synthetic challenge. The development of such a methodology would provide a dramatically streamlined route to valuable, highly functionalized alkane structures, such as the 1,1‐diaryl motif, which is a privileged scaffold in medicinal chemistry and materials science [22, 23, 24, 25, 26, 27]. Despite its clear utility, a general catalytic protocol for the saturative trifunctionalization of alkynes remains underdeveloped (Figure 1a, right). The core difficulties lie in achieving simultaneous control over regioselectivity, chemoselectivity, and the final reductive event, all without compromising functional group compatibility or reaction efficiency.

FIGURE 1.

Evolution of alkyne functionalization. (a) Difunctionalization and multi‐functionalization of alkynes; (b) Boron‐mediated functionalization of alkynes; (c) Boron‐mediated saturative trifunctionalization of alkynes (this work).

To address these selectivity hurdles, we turned to organoboron chemistry [28, 29, 30, 31, 32, 33, 34, 35], which offers a powerful means to govern regioselectivity through the unique properties of boron. The evolution of organoboron reagents—from simple coupling partners to sophisticated selectivity‐directing mediators—has been pivotal, leveraging their stability, low toxicity, and synthetic versatility. A key development in this area involves the use of alkynyl tetracoordinate boron species, whose unique electronic properties unlock unconventional alkyne functionalization pathways that have proven highly successful for accessing substituted alkenes. For instance, Murakami et al. pioneered a palladium‐catalyzed reaction between alkynyl tetracoordinate borons and aryl halides to produce diversely substituted alkenes [36, 37, 38, 39, 40, 41, 42, 43, 44]. Subsequently, our group established a method for the stereodefined assembly of polysubstituted alkenes using such reagents via Ni catalysis [37]. Recent contributions from Aggarwal [40, 41, 42] and Lalic [43, 44] groups have introduced additional catalytic systems to access multisubstituted alkenes from these boron precursors (Figure 1b, left). However, extending this boron‐mediated logic to alkane synthesis poses a distinct challenge: the common termination steps in these catalytic cycles (e.g., β‐hydride or β‐boron elimination) naturally lead to olefins. Achieving a saturative outcome requires intercepting the reaction sequence to prevent elimination and instead forge two new C─C bonds at the same carbon center. Consequently, a general catalytic protocol for the saturative trifunctionalization of alkynes remains elusive (Figure 1b, right).

Herein, we report a boron‐mediated, nickel‐catalyzed strategy for the saturative trifunctionalization of alkynes, providing a concise route to valuable 1,1‐diarylalkanes from simple precursors (Figure 1c). This transformation begins with the conversion of an alkyne into an alkynyl tetracoordinate boron complex (which may be used in situ or isolated). This intermediate then engages a N‐acylglutarimide derivative as a bifunctional coupling partner. Mechanistic studies outline a catalytic cycle initiated by oxidative addition to form Int‐I, followed by a distintive sequence of migratory insertions and rearrangements (via Int‐II to Int‐IV through Int‐III) that inherently minimizes byproduct formation. Critically, control experiments exclude an alternative pathway involving direct alkyne insertion into Int‐I, corroborating the proposed mechanism. This carefully orchestrated sequence delivers the saturated products with high regio‐ and chemoselectivity. This work extends the utility of boron‐mediated selectivity control from alkene to alkane synthesis. It reveals a saturative termination pathway in nickel catalysis, moving beyond standard coupling products. Overall, it provides a viable platform for the assembly of complex saturated frameworks from alkynes, a transformation that may find applications in medicinal and materials chemistry [22, 23, 24, 25, 26, 27].

2. Results and Discussion

2.1. Optimization of the Reaction Conditions

To establish an efficient and modular approach for the saturative trifunctionalization of alkynes, we commenced our study by employing alkynyl tetracoordinate boron (A1) as the readily accessible starting material and 1‐benzoylpiperidine‐2,6‐dione (B1) as the acylating reagent [45]. The reaction was performed in THF at 40°C for 12 h in the presence of NiCl₂ ·DME as the catalyst, 2‐(quinolin‐2‐yl)‐4,5‐dihydrooxazole (L1) as the ligand, Ph₂SiH₂ as the reductant and LiCl as an additive. Under these conditions, the desired 1,1‐diarylalkane 1 was isolated in 86% yield (Table 1, entry 1). The structure of compound 1 was unambiguously confirmed by X‐ray crystallographic analysis (CCDC: 2523893). Replacement of the nickel catalyst with Ni(cod)₂ or Ni(acac)₂ led to diminished efficiency (entries 2, 3). Similarly, substitution of Ph₂SiH₂ with DEMS or PMHS [46] resulted in lower reactivity (entries 4, 5), and omission of the silane reductant severely impaired the reaction (entry 6). Exchanging LiCl for ZnCl₂ [47] completely inhibited product formation (entry 7), whereas the absence of LiCl only slightly reduced the yield (entry 8). These results indicate that LiCl acts as an effective promoter in this boron‐mediated transformation, while ZnCl₂ is unsuitable. Switching THF to other ether solvents such as CPME or DME lowered the yield without affecting chemoselectivity (entries 9, 10). Notably, the use of rigorously dry THF significantly decreased the yield (entry 11), highlighting the beneficial role of trace amount of water. Increasing the temperature or lowering the concentration also proved detrimental (entries 12, 13). Finally, a range of nitrogen‐ and phosphorus‐based ligands commonly employed in Ni‐catalyzed functionalizations were evaluated (L2–L9, see bottom of Table 1). Nitrogen donors generally outperformed phosphine ligands in this system, with the original oxazoline ligand L1 consistently affording the best results. Thus, the conditions in entry 1 were identified as optimal for the saturative trifunctionalization of alkynes.

TABLE 1.

Optimization of the reaction conditions ^a .

Entry	Reaction conditions deviation	Yield of 1 (%) b
1	none	86 (81) c
2	Ni(cod)2 was used instead of NiCl2 • DME	83
3	Ni(acac)2 was used instead of NiCl2 • DME	62
4	DEMS instead of Ph2SiH2	54
5	PMHS instead of Ph2SiH2	16
6	Without Ph2SiH2	20
7	ZnCl2 instead of LiCl	0
8	Without LiCl	72
9	CPME instead of THF	36
10	DME instead of THF	79
11	dry THF instead of regular THF	16
12	80°C instead of 40°C	41
13	0.05 M instead of 0.1 M	60

^a Reaction conditions: The reaction was carried out with alkynyl tetracoordinate boron (A1, 0.1 mmol, 1.0 equiv), 1‐benzoylpiperidine‐2,6‐dione (B1, 0.15 mmol, 1.5 equiv), NiCl₂ ·DME (10 mol%), ligand (20 mol%), Ph₂SiH₂ (0.25 mmol, 2.5 equiv), LiCl (0.3 mmol, 3.0 equiv) in 1 mL of THF at 40°C for 12 h.

^b Yields were determined by GC analysis using n‐dodecane as an internal standard.

^c Isolated yield. DEMS: diethoxymethylsilane; PMHS: polymethylhydrosiloxane.

2.2. Substrate Scope

Having established the optimized reaction conditions, we next evaluated the substrate scope of this catalytic saturative trifunctionalization (Figure 2). We first examined modifications to the aryl ring of the N‐acylglutarimide reagents (B). Pleasingly, the catalytic system demonstrated good functional group tolerance. A variety of substituents were compatible, affording the corresponding products 1–13 in good yields. This included alkyl groups (methyl 2, isopropyl 3, tert‐butyl 4), common electron‐donating groups (methylthio 5, dimethylamino 6), and challenging electron‐withdrawing groups (difluoromethoxy 7, trifluoromethoxy 8, trifluoromethyl 9, fluorine 10, chlorine 11, bromine 12), as well as an extended aryl system (phenyl 13). Notably, the aryl bromide substrate [27, 28] was efficiently converted to product 12, with the process favoring the boron‐mediated double‐migration pathway over a competing single migration, highlightingthe excellent chemoselectivity of this method. We then investigated meta‐ (14) and ortho‐substituted (15) aryl rings. Both were well tolerated, and the reaction proved insensitive to steric hindrance (15). Polysubstituted N‐acylglutarimides (16–22) and fused‐ring (23, 24) proved to be suitable substrates, delivering the corresponding polysubstituted alkanes in satisfactory yields (61%–80% yield). When using 1‐(3‐methoxybenzoyl)piperidine‐2,6‐dione (B2) as the substrate, alkynyl tetracoordinate boron substrates (A) bearing varied substituents were all compatible, furnishing products 25–28 in 65%–75% yield. Furthermore, with 1‐benzoylpiperidine‐2,6‐ dione (B1) as the substrate, a variety of alkynyl tetracoordinate boron reagents—including differentially substituted phenethyl, naphthyl, and disubstituted phenyl derivatives—were also evaluated and delivered the desired products (29–38) in similarly satisfactory outcomes.

FIGURE 2.

Substrate scope. Reaction conditions: The reaction was carried out with alkynyl tetracoordinate boron (A, 0.1 mmol, 1.0 equiv), N‐acylglutarimide (B, 0.15 mmol, 1.5 equiv), NiCl₂·DME (10 mol%), L1 (20 mol%), Ph₂SiH₂ (0.25 mmol, 2.5 equiv), LiCl (0.3 mmol, 3.0 equiv) in 1 mL of THF at 40°C for 12 h.

To further demonstrate the generality of the reaction system and access a broader array of structurally diverse polysubstituted alkanes, we systematically evaluated the substrate scope with respect to the alkynyl tetracoordinate boron component (A) with 1‐(4‐(tert‐butyl)benzoyl)piperidine‐2,6‐dione (B4) (Figure 3). Initially, aryl‐substituted alkynyl tetracoordinate borons were examined and proved to be excellent substrates under our nickel‐catalyzed conditions, affording the corresponding products 39–43 in good yields. Subsequently, readily accessible alkynyl tetracoordinate borons with diverse alkyl substituents were investigated. Substrates bearing halogen (44), cyano (45), ether (46), and cycloalkyl (47–48) functionalities were all well tolerated. Notably, an enynyl substrate was also efficiently converted to product 49 in moderate yield. Next, a series of ester‐containing alkynyl tetracoordinate boron substrates were explored. Variations on the aromatic ring of these esters were compatible, delivering products 50–58 in moderate to good yields. The system also accommodated a substrate containing an additional C═C bond, successfully yielding 59 and thereby demonstrating excellent chemoselectivity. Disubstituted and trisubstituted substrates reacted smoothly, providing products 61–66. Good yields (70% and 81%) were obtained even with hydrogen or bromine at the 1 position of a naphthalene ring (67, 68). Diverse ether‐ and thioether‐containing substrates were efficiently converted under the standard conditions to give 69–74 in 70%–79% yield. Furthermore, heterocyclic scaffolds and pharmaceutically relevant motifs exhibited excellent compatibility furnishing products 75–79, thereby underscoring the applicability of this transformation. Finally, the generality of the migration process was probed using a range of migrating groups. Aromatic rings bearing electron‐donating or electron‐withdrawing substituents, as well as heterocyclic groups, all underwent efficient conversion to the corresponding products (80–86) with high efficiency. Collectively, the results in Figures 2 and 3 demonstrate that this boron‐mediated process is effective for saturative trifunctionalization of a range of alkynes. It accommodates many electronically diverse and sterically demanding substituents, heterocycles, and pharmaceutically relevant motifs, enabling the assembly of functionalized 1,1‐diarylalkanes that can be cumbersome to access via traditional stepwise approaches [22, 23, 24, 25, 26, 27]. It should be noted that attempts to replace the N‐acylglutarimide with other electrophiles (e.g., aryl halides, acyl chlorides, alkyl halides) under the standard conditions were unsuccessful, indicating that the current protocol is specifically tailored to this bifunctional coupling partner (see SI for details).

FIGURE 3.

Substrate scope. Reaction conditions: the reaction was carried out with alkynyl tetracoordinate boron (A, 0.1 mmol, 1.0 equiv), 1‐(4‐(tert‐butyl)benzoyl)piperidine‐2,6‐dione (B4, 0.15 mmol, 1.5 equiv), NiCl₂·DME (10 mol%), L1 (20 mol%), Ph₂SiH₂ (0.25 mmol, 2.5 equiv), LiCl (0.3 mmol, 3.0 equiv) in 1 mL of THF at 40°C for 12 h.

2.3. Downstream Applications and Transformations

To underscore the synthetic utility and practicality of this method, we developed streamlined applications that highlight its efficiency and integration potential (Figure 4). A one‐pot procedure was developed. Using terminal alkyne A4' as the starting material, sequential deprotonation and borylation, followed by reaction with 1‐(4‐(tert‐butyl)benzoyl)piperidine‐2,6‐dione (B4) under the standard conditions, afforded the desired product 4 in 70% yield upon the addition of an additional 5 µL of water. (Figure 4a). This result demonstrates that the overall transformation can be executed from a simple terminal alkyne without isolation of the intermediate alkynyl tetracoordinate boron, supporting the feasibility of a direct‐type protocol, although most substrate scope studies were conducted with preformed boron complexes. Subsequently, the protocol was applied to the late‐stage functionalization of two drug‐derived molecules, Veratraldehyde and Adapalene, delivering the corresponding targets 87 and 88 in 80% and 76% yields, respectively (Figure 4b). Scalability was then examined: gram‐scale reactions proceeded smoothly to furnish products 89 and 90 in 70% and 68% yield, respectively (Figure 4c). The synthetic value of the products was further highlighted through diverse downstream transformations. Using 89 as the substrate, Suzuki coupling proceeded in 79% yield to give 91. Coupling reactions with phenol and carbazole, as well as Wittig olefination, Heck coupling, Miyaura borylation, reductive coupling, and Sonogashira reactions, all proceeded efficiently to provide the corresponding derivatives 92–98 in good yields. Additionally, substrate 90 was successfully subjected to carbonyl reduction and Wittig reaction, yielding the corresponding alcohol and olefin (99 and 100) in 52% and 73% yield, respectively. These transformations collectively underscore the versatility and synthetic potential of the products accessible through this boron‐enabled migration platform.

FIGURE 4.

Synthetic applications and derivatizations. (a) One‐pot synthesis starting from a terminal alkyne. (b) Late‐stage functionalization of drug derivatives. (c) Gram‐scale reactions. (d) Diverse downstream transformations of products 89 and 90.

2.4. Synthetic Significance

To our knowledge, no catalytic protocol has yet achieved the direct, saturative trifunctionalization of alkynes to fully substituted alkanes in a single operation. The present nickel‑catalyzed, boron‑mediated strategy fills this gap. Beyond its mechanistic novelty (the first example of a saturative dual 1,2‑metallate shift), the method offers several practical advantages: (i) mild conditions (40 °C) using an inexpensive Ni catalyst and a stable silane, avoiding air‑sensitive reagents or strong bases; (ii) good functional group tolerance (Br, CN, ester, thioether, free NH, heterocycles) as shown in Figures 2 and 3; (iii) a one‑pot protocol from a terminal alkyne (Figure 4a, 70% yield); (iv) high‑level deuterium incorporation (>99% D) using cheap D₂O; and (v) a ketone handle that enables diverse downstream transformations (Figure 4d). These features provide a complementary and synthetically useful approach to 1,1‑diarylalkanes, especially for functionalized substrates that are challenging for existing methods.

2.5. Mechanism Investigations

Mechanistic studies were undertaken to elucidate the pathway responsible for the unique saturative outcome, which stands in contrast to the more common olefin‐forming manifolds in boron‐migration chemistry (Figure 5). Toward this end, control experiments and analysis of the reaction mixture were first conducted. In the absence of both the metal catalyst and the ligand, the model reaction did not proceed. Furthermore, analysis of the post‐reaction mixture from the model reaction via in situ ^{1 1}B NMR spectroscopy and HRMS confirmed the presence of phenylboronic acid and its chlorinated adduct (Figure 5a). These findings support an intramolecular rather than intermolecular process and indicate that chloride ions can coordinate to the tricoordinate boron species to form a tetracoordinate boron compound (Figure 5a). Deuterium‐labeling experiments were then performed. Adding D₂O (20 equiv) to the model substrates resulted in deuterium incorporation at the relevant position with 90% D‐incorporation, furthermore, a series of deuterium‐labeling control experiments were performed to probe the feasible reaction mechanism. Even in the presence of excessive proton sources, the once‐metallate‐shift products mediated by transition‐metal catalysis remained inaccessible. Meanwhile, this protocol affords a simple and facile approach toward the efficient construction of 1,2‐dideuterated alkanes with >99% deuterium incorporation (Please see Supplementary 5.2 for more details). These results further highlight the synthetic utility of our transformation and endow the developed reaction strategy with potential for further applications [48, 49, 50]. In contrast, employing deuterated silane (Ph₂SiD₂) as the additive led to 0% D‐incorporation (Figure 5b). These results confirm that the hydrogen in the product originates from water, not from the silane, and effectively rule out the involvement of a nickel‐hydride species [37] (which would typically add across unsaturated bonds), thereby excluding a conventional hydrometallation/insertion pathway that typically leads to alkene products. Further investigation employed designed substrates A104 and A105 in an attempt to trap potential intermediates; however, the desired cyclized or trapped products were not observed (Figure 5c, equation 1). Notably, species 101–103 were detected by GC‐MS or HRMS analysis of the standard reaction mixture (Figure 5c, equation 2). Based on these mechanistic insights and known reactivity [39, 40, 41, 42, 43, 44, 51, 52, 53, 54, 55, 56], a plausible catalytic cycle is proposed. Initially, Ni(II) is reduced to Ni(I) by silane, followed by oxidative addition of the N‐acylglutarimide with the Ni(I) species to form Int‐I. [57, 58] This electrophilic nickel complex then activates the alkyne moiety of the alkynyl tetracoordinate boron, inducing a 1,2‐migration to deliver Int‐II. A cis‐addition pathway of Int‐I across the alkyne is ruled out based on the trapping experiment (Figure 5c, equation 1). Subsequent reductive elimination from Int‐II yields vinylboron species Int‐III and regenerates nickel(I). In the presence of chloride ions, OH⁻ or glutarimide ions, Int‐III is converted to a vinyl tetracoordinate boron, which undergoes a second nickel‐mediated 1,2‐migration to afford intermediate Int‐IV [59, 60]. Finally, hydrolysis of Int‐IV releases the desired product and completes the catalytic cycle. Critically, the final intermediate (Int‐IV) escapes the typical fate of β‐boron elimination, which would yield an alkene. Instead, hydrolysis terminates [36, 37, 38] the sequence, securing the saturated product. This divergence—where hydrolysis outcompetes elimination—is the key to achieving the unprecedented saturative trifunctionalization.

FIGURE 5.

Mechanistic investigations and proposed catalytic cycle. (a) Control experiments and analysis of reaction mixture. (b) Deuterium‐labeling studies. (c) Intermediate trapping and detection of key species. (d) Proposed catalytic cycle involving dual 1,2‐metallate shifts. ^a H₂O (10 equiv) was involved in our catalytic system. ^b The reaction was conducted for 3 h under the standard reaction conditions.

3. Conclusions

In summary, we have developed a general and catalytic strategy for the saturative trifunctionalization of alkynes, providing concise access to synthetically challenging and medicinally relevant 1,1‐diarylalkanes. This work bridges a significant gap between the well‐established difunctionalization of alkynes to alkenes and the elusive goal of directly constructing complex, fully saturated architectures. The success of this transformation hinges on the synergistic combination of nickel catalysis with the unique reactivity of alkynyl tetracoordinate borons. This partnership orchestrates a carefully controlled sequence involving two distinct 1,2‐aryl migrations, ultimately terminated by hydrolysis. Mechanistic investigations rule out alternative pathways involving nickel‐hydride species or direct cis‐addition, confirming the proposed migratory mechanism. Critically, the system avoids the competing β‐boron elimination, a common pathway that would lead to olefins, thereby ensuring the unique saturative outcome. Further investigations will be devoted to exploring asymmetric multiple metallate migration reactions enabled by transition‐metal catalysis.

Author Contributions

Shanglin Chen: investigation, validation, writing – original draft, formal analysis. Yaru Peng: investigation, validation. Junmei Lin: investigation, validation. Puhui Li: investigation, validation. Daojun Ye: investigation, validation. Yuhan Wang: investigation, validation. Xingxing Ma: writing – original draft, funding acquisition, supervision, writing – review and editing. Qiuling Song: conceptualization, methodology, funding acquisition, project administration, supervision, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

The authors have cited additional references within the Supporting Information [1–24].

Supporting File 1: anie72836‐sup‐0001‐SuppMat.pdf.

Supporting File 2: anie72836‐sup‐0002‐cif.zip.

Data Availability Statement

The data that supports the findings of this study are available in the Supporting information of this article.