Regiocontrolled hydrobromination of unactivated alkenes via direct and chain-walking pathways

Abstract

The development of regioselective methods for C(sp³)─Br bond formation in unactivated alkenes remains a fundamental challenge in organic synthesis. Herein, we report a nickel hydride–catalyzed method that enables regiocontrolled hydrobromination of both terminal and internal alkenes through strategic deployment of an N-fluoropyridinium oxidant. The method features two complementary approaches: direct hydrobromination of alkenes with high proximal selectivity and a chain-walking strategy that enables switchable site-selective functionalization in extended alkyl chains. Notably, temperature-controlled reaction parameters enable regiodivergent access to β- or γ-brominated products from identical alkenes with excellent selectivity. The protocol demonstrates broad functional group tolerance and enables late-stage functionalization of pharmaceuticals. Mechanistic studies, including deuterium labeling, radical clock experiments, and density functional theory calculations, revealed a radical-mediated pathway featuring temperature-dependent regioselectivity in the chain-walking process. This unified method provides a versatile platform to access diverse alkyl bromides and offers fundamental insights into selective C─Br bond construction through direct and chain-walking pathways.

Nickel hydride–catalyzed hydrobromination of unactivated alkene achieves proximal and chain-walking regioselectivity.

INTRODUCTION

Alkyl bromides serve as indispensable building blocks in organic synthesis, finding extensive applications in both industrial processes and academic research (1–6). The synthetic versatility of the C(sp³)─Br bond enables diverse downstream transformations, such as in nucleophilic substitution reactions and transition metal–catalyzed cross-coupling processes (7–13). Consequently, the development of efficient methods for alkyl bromide synthesis remains an active area of research with notable practical implications. Traditional alkyl bromide synthesis relies on two main approaches: nucleophilic substitution of alcohols (14–16) and direct hydrobromination of alkenes (17, 18). The latter method offers key advantages, including atom economy and access to diverse molecular scaffolds. This approach is attractive given the abundant availability and economic viability of unactivated alkenes as feedstock materials. However, conventional acid-mediated hydrobromination protocols have substantial limitations: poor regioselectivity with internal alkenes and limited functional group tolerance due to the required strongly acidic conditions (Fig. 1A).

Fig. 1. Hydrobromination of internal alkenes.

(A) Challenges in regioselectivity. (B) Previous methods for site-selective C─Br bond formation. (C) Working hypothesis of this work: regiocontrolled alkene hydrobromination through both direct and chain-walking pathways.

Recent developments have addressed several of these challenges in alkene hydrohalogenation (Fig. 1B). Liu and coworkers achieved remote hydrohalogenation at terminal positions using palladium-hydride intermediates, (19) optimizing selectivity through ligand design. To control regioselectivity in internal alkenes, the Yudin group leveraged the β-boron effect for electrophilic addition (20). Recently, Shibutani et al. (21) developed a cobalt-catalyzed metal-hydride hydrogen atom transfer (MHAT) system showing Markovnikov selectivity, particularly at tertiary carbons. Jankins et al. (22) also developed a cobalt-catalyzed shuttle HAT strategy for transferring of halogen atom. However, in both cases, precise regiocontrol in unactivated alkene functionalization, especially with internal alkenes, remains challenging. This limitation arises from the difficulty in differentiating electronically similar carbon centers, hampering the development of general methods for branch-selective hydrobromination.

To address this limitation in synthetic methodology, we proposed a nickel hydride–catalyzed method for the regioselective formation (23–26) of C(sp³)─Br bonds. However, our initial attempts using N─Br reagents such as NBS were unsuccessful because these reagents exhibit much lower oxidizing ability compared to N─F reagents and lack sufficient oxidative power to generate the necessary Ni intermediates at the oxidative addition step. To overcome this challenge, we envisioned the strategic utilization of in situ–generated bromine radicals (Fig. 1C). This approach requires a suitable oxidant that serves a dual role: generating bromine radicals via controlled bromide oxidation while enabling nickel catalyst turnover (27). Our group previously demonstrated the efficacy of N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (NFTPT) functions as both a nickel catalyst oxidant and fluorine source in hydrofluorination reactions (28). Recently, the Zhu group reported the application of NFTPT as a single-electron oxidant in copper-catalyzed MHAT processes (29). Building upon these precedents, we hypothesized that regiocontrolled hydrobromination could be achieved through selective generation of bromine radicals via single-electron oxidation of bromide with NFTPT rather than through oxidative addition to the nickel catalyst. Crucially, the innovative electron donor-acceptor (EDA) complex formation between NFTPT and bromide enables inherent control through reversible single-electron transfer (SET)/back electron transfer (BET), allowing precise manipulation of bromine radical generation and preventing side product formation such as dibromides. Here, we present a nickel-catalyzed regioselective hydrobromination of unactivated alkenes, enabling modular synthesis of diverse branched alkyl bromides from both terminal and internal alkenes. Furthermore, we have developed a switchable site-selective hydrobromination for extended-chain alkenes using controlled chain-walking, a cutting-edge approach attracting considerable interest in contemporary research (30–39). This regiodivergent approach accesses either β- or γ-branched alkyl bromides from identical substrates through manipulation of thermodynamic and kinetic parameters (40).

RESULTS

Reaction development of direct hydrobromination

To develop our proposed method, we initially investigated the hydrobromination of model substrate 1a with LiBr under various conditions (Fig. 2). Through systematic optimization, we identified the optimal reaction conditions: a nickel catalyst with BOX ligand L1, NFTPT as the oxidant, and dimethoxymethylsilane as the hydride source in isopropyl acetate at room temperature, which provided product 2c. The choice of the oxidant proved crucial for the efficiency of the reaction. Alternative oxidants led to substantial dibromination (entries 2 to 4, see table S7), while triflate counteranion–containing oxidants yielded only 9% of 2c. The tetrafluoroborate (BF₄⁻) counterion was essential for optimal performance, with LiBF₄ addition enhancing reactivity, likely by facilitating NiH species generation (entry 5). Investigation of LiBr stoichiometry showed that lower quantities decreased reactivity and led to competing hydrofluorination (entries 6 and 7). This side reaction was suppressed by using 2.0 equiv of LiBr, affording 2c in 67% yield. This controlled radical pathway effectively suppresses hydrofluorination side reactions as the single-electron reduction of NFTPT generates pyridyl radical cations with concomitant release of innocent fluoride anions, (41), which remain unreactive under the reaction conditions. Control experiments demonstrated the necessity of each reaction component as no product was observed in the absence of nickel catalyst, silane, or oxidant (entry 9).

Fig. 2. Optimization of the reaction conditions.

Reaction conditions: 1a (0.1 mmol), LiBr (2.0 equiv), [Ox] (2.0 equiv), Ni(ClO₄)₂•6H₂O (10 mol %), ligand (12 mol %), (MeO)₂MeSiH (2.0 equiv), H₂O (1.5 equiv) in solvent (0.5 ml) at room temperature (rt) for 18 hours (h) under argon. Yields and regioisomeric ratios were determined by ¹H nuclear magnetic resonance (NMR) analysis of crude mixture with 1,3,5-trimethoxybenzene as an internal standard.

Substrate scope of direct hydrobromination

Having established optimal conditions, we explored the substrate scope of this transformation (Fig. 3). The method showed broad tolerance across diverse unactivated alkenes, delivering desired products with high regioselectivity. Terminal and internal alkenes with various hydrocarbon substituents (Me, Et, n-Bu, and cyclopropyl) at the terminal position gave the corresponding products in good yields with excellent regioselectivity (2a to 2f). A 0.5-mmol scale reaction delivered the desired product 2c in 59% yield with maintained selectivity, showing reasonable scalability despite a slight reduction in yield. A substrate with a sterically demanding cyclohexyl group (2g) provided a slightly lower yield while maintaining high regiocontrol. Notably, substrates containing potential directing benzylic sites underwent selective β-bromination, demonstrating the method’s chemoselectivity (2i). The protocol showed excellent functional group tolerance, successfully accommodating phthalimide, alcohol, and ester groups—features valuable for complex molecule synthesis (2j to 2l). Terminal alkenyl amides with various electronic substituents on the aryl ring were also well-tolerated (2m to 2p). Substrates containing gem-dimethyl substitution at the α position underwent selective hydrobromination to give β-brominated products exclusively (2q). Various amide derivatives, including β,γ-allylic amides (2r to 2t) and γ,δ-alkenyl amides (2u), showed distinct regioselectivity patterns, with γ,δ-alkenyl amides selectively yielding γ-brominated products (2v and 2w). Moreover, our current approach enables the efficient construction of β-brominated ketones from β,γ-alkenyl ketone and ester substrates (2x and 2y). To demonstrate synthetic utility, we applied this method to late-stage functionalization of pharmaceutical derivatives. The protocol effectively achieved regioselective hydrobromination of complex alkenes in various drug derivatives, including probenecid (2z), isoxepac (2aa), ibuprofen (2ab), gemfibrozil (2ac), indomethacin (2ae), and phenylalanine derivatives (2ad), highlighting its potential in medicinal chemistry applications.

Fig. 3. Substrate scope of direct hydrobromination.

Reaction conditions of direct hydrobromination: 1 (0.1 mmol), LiBr (2.0 equiv), [Ox]-1 (2.0 equiv), Ni(ClO₄)₂•6H₂O (10 mol %), L1 (12 mol %), (MeO)₂MeSiH (3.0 equiv), H₂O (1.5 equiv), and ⁱPrOAc (0.5 ml) at room temperature (rt) for 18 hours under argon. Isolated yields. Regioisomeric ratios determined by ¹H NMR. Ar = 4-CO₂EtPh. ^aReaction was conducted in 0.5-mmol scale.

Reaction development of chain-walking hydrobromination

We then explored regioselective hydrobromination at remote positions beyond β,γ and γ,δ carbons through nickel-catalyzed chain-walking (Fig. 4). Initial utilization of direct hydrobromination conditions afforded γ- and β-brominated products (4a and 5a) in a 3.6:1 ratio (51 and 14% yield, entry 2). Changing nickel source proved efficient for regioselectivity; substitution of Ni(ClO₄)₂•6H₂O with Ni(BF₄)₂•6H₂O enhanced the γ/β ratio to 18:1 while modestly improving yield. Also, we achieved an enhanced yield of 75% by reducing the catalyst loading. We found that ligand structure influences product distribution, with replacement of 3,5-di^tBuPh (L1) by 3,5-diMePh (L2) leading to nearly equal formation of γ and β products (23 and 25%, respectively, entry 4). This observation led us to further investigate the β-bromination reaction. Further optimization studies revealed a remarkable temperature dependence of product selectivity (Fig. 4, graph). Employment of ligand L2 with NiBr₂•diglyme demonstrated a notable correlation between reaction temperature and regioselectivity: Increasing the temperature from 20° to 80°C resulted in predominant formation of β-product 5a with excellent selectivity (>20:1 regioisomeric ratio) and complete conversion within 4 hours. The temperature dependence of chain-walking provides mechanistic insight, revealing that regioselectivity is controlled by thermal activation energy—Higher temperatures provide sufficient energy to overcome the activation barrier for β-product formation. Subsequently, the introduction of H₂O and Na₂HPO₄ proved optimal, furnishing the desired β-product 5a in 74% yield while maintaining high regioselectivity. These findings underscore the critical role of comprehensive reaction parameter optimization in controlling hydrobromination outcomes.

Fig. 4. Optimization of the reaction conditions.

Reaction conditions: 3 (0.1 mmol), LiBr (2.0 equiv), [Ox]-1 (2.0 equiv), Ni(BF₄)₂•6H₂O (7.5 mol %), ligand (9 mol %), (MeO)₂MeSiH (3.0 equiv), and solvent (0.5 ml) at 20°C for 18 hours. ^bReaction conditions: 3 (0.1 mmol), LiBr (1.5 equiv), [Ox]-1 (1.5 equiv), NiBr₂•diglyme (12.5 mol %), ligand (15 mol %), (MeO)₂MeSiH (3.0 equiv), H₂O (2.0 equiv), and solvent (0.5 ml) at various temperature for 4 hours. Yields and regioisomeric ratios determined by 1H NMR of crude mixture with 1,3,5-trimethoxybenzene as an internal standard.

Substrate scope of chain-walking hydrobromination

With optimized conditions established for both γ- and β-selective chain-walking processes, we next explored the generality of this transformation across diverse substrate classes (Fig. 5). The γ-selective protocol showed broad applicability with homologous alkenyl amides from C6 to C10 chain lengths, giving γ-brominated products with high selectivity (4a to 4e). Notably, we observed minimal β-brominated regioisomer formation and complete suppression of bromination at ipso, δ, and α positions. This selectivity pattern extended to δ,ε-alkenes with various substituents on the amide aryl group. The methodology tolerated diverse functional groups, including both electron-donating (4f, 4j, and 4k) and electron-withdrawing (4g, 4h, 4i, and 4l) substituents at para and meta positions. Notably, aryl iodides (4i) afforded the desired product despite their tendency toward oxidative addition to nickel. Alkenyl amides with trisubstituted aryl moieties showed moderate reactivity (4m). Extended-chain alkenes with diverse para-substituents proved viable, including both electron-rich (4p) and electron-deficient (4n and 4o) aromatics. α-Substituted alkenyl amides bearing methyl (4r), benzyl (4s), and chlorinated alkyl (4t) groups underwent functionalization with maintained regioselectivity. Benzamide also directed bromination to the γ position with high selectivity (4q). The γ-selective protocol effectively achieved late-stage functionalization of pharmaceutical derivative flufenamic acid (4u), providing brominated products with excellent positional selectivity. These results demonstrate the broad utility of our chain-walking hydrobromination strategy across diverse structural motifs.

Fig. 5. Substrate scope of chain-walking hydrobromination.

Condition A: 1 (0.1 mmol), LiBr (2.0 equiv), [Ox]-1 (2.0 equiv), Ni(BF₄)₂•6H₂O (7.5 mol %), L1 (9.0 mol %), (MeO)₂MeSiH (3.0 equiv), and ⁱPrOAc (0.5 ml) at 20°C under argon atmosphere for 18 hours. Condition B: 1 (0.1 mmol), LiBr (1.5 equiv), [Ox]-1 (1.5 equiv), NiBr₂•diglyme (12.5 mol %), L2 (15 mol %), (MeO)₂MeSiH (3.0 equiv), H₂O (2.0 equiv) and ⁱPrOAc (0.5 ml) at 80°C under argon atmosphere for 4 hours. Isolated yields. Regioisomeric ratio was determined by ¹H NMR analysis.

Following the success of γ-selective hydrobromination, we investigated the β-selective transformation across diverse substrate classes. We applied this protocol to alkenes previously performed under γ-selective conditions, enabling direct comparison of regioselectivity and yield between both methods. Homologous alkenyl amides (C5 to C10) underwent efficient β-selective hydrobromination, giving the desired products as single regioisomers (5a to 5e). The protocol showed broad functional group tolerance, accommodating both electron-rich and electron-deficient substituents at para and meta positions of the aromatic ring (5f to 5l). Alkenes with extended chain lengths maintained high regioselectivity, independent of the electronic properties of para-substituents on the aromatic ring (5m to 5o). α-Substituted alkenyl amides with methyl (5q), benzyl (5r), and dimethyl (5s) groups proved viable substrates, providing the corresponding products in good yields. The chain-walking process also enabled β-selective hydrobromination in γ,δ-alkenes (5u and 5v). Alternative directing groups, including benzamide (5p and 5t), provided products in synthetically useful yields. Notably, substrates 5t, 5u, and 5v exhibited different selectivity compared to those obtained using our direct hydrobromination protocol. In addition, cyclic alkene substrates also demonstrated the chain-walking process to the β position (5w). These results highlight that controlled regioselectivity can be achieved from the same alkene substrates under the β-selective chain-walking reaction conditions. To demonstrate utility, we applied this chain-walking hydrobromination protocol to late-stage functionalization of flufenamic acid derivatives (5x).

Mechnistic investigations

We conducted a series of mechanistic investigations to probe the reaction pathway (Fig. 6). Initial studies focused on radical involvement: addition of TEMPO (1.0 equiv) completely suppressed the reaction, suggesting participation of radical intermediates (Fig. 6A). This hypothesis was further supported by the formation of cyclized product 6a from diethyl diallylmalonate under optimized conditions, consistent with Br radical intermediacy (Fig. 6B, top). Control experiments without nickel, ligand, and silane showed formation of ring-opened product 7a upon radical trap addition, indicating Br radical generation through SET between NFTPT and LiBr (Fig. 6B, bottom). Direct use of complex Ni-L (10 mol %) gave product 2p (7%) with concurrent formation of fluorinated byproduct (38%) in the absence of Br source (Fig. 6C). Increasing complex loading to 100 mol % suppressed fluorination, giving 2p in 51% yield, indicating that bromination is favored with excess Br source. Carbon radical formation via Ni─C bond homolysis (42–45) was demonstrated by isolation of cyclized product 8a from diene substrate under standard conditions (Fig. 6D). To distinguish between potential mechanistic pathways and investigate nickel oxidation states, we studied alcohol-substituted alkenyl amides as mechanistic probes. While initial results suggested a radical-mediated S_H2 pathway, we also investigated the possibility of NFTPT-mediated oxidation-generating Ni(IV) species, which could enable S_N2-type reactivity similar to carbocation intermediates (Fig. 6E) (46–49). However, the absence of hydroalkoxylation product 9b suggests that both a carbocation and an alkyl Ni(IV) complex are unlikely to be involved in the reaction mechanism. To gain deeper insights into the reaction characteristics, a series of deuterium labeling experiments were conducted. Chain-walking hydrobromination of alkene 3a was performed using dimethoxymethylsilane-d (DMMS-d) (Fig. 6F). Analysis of the product revealed deuterium incorporation at both ε and δ positions, with notably higher deuterium content consistently observed at the ε positions. Investigation of the chain-walking process using deuterium-labeled substrate ε,ε-d₂-3a′ showed no deuterium incorporation at α to γ positions or α,β positions under both selective conditions (Fig. 6G). These results demonstrate directional migration from δ to β position, with nickel exclusively migrating toward the carbonyl coordination site (40, 50). The formation of an EDA complex between NFTPT and bromide (see the Supplementary Materials) is crucial to this reaction system. This complex formation was confirmed through ultraviolet-visible (UV-Vis) spectroscopy, which revealed characteristic absorption bands, and further validated by nuclear magnetic resonance (NMR) studies. Collectively, these mechanistic studies provide evidence for a radical-mediated pathway, elucidating key mechanistic features including: (i) Br radical generation through NFTPT-LiBr interaction, (ii) carbon radical formation via Ni─C bond homolysis, and (iii) directional chain-walking process governed by carbonyl coordination.

Fig. 6. Mechanistic investigations.

(A) Radical inhibition experiment. (B) Radical-clock investigation. (C) Reaction with nickel complex. (D) Reaction with diene. (E) Distinguishment of RPC-S_N2 versus S_H2/R.E. pathway. (F) Deuterium-labeling experiment using DMMS-d. (G) Deuterium labeling experiment using D-subsituted alkene. n.d./N.D., not detected.

On the basis of our mechanistic studies, we propose a catalytic cycle for the regioselective nickel-catalyzed hydrobromination (Fig. 7A) (51). The cycle begins with formation of LNi(II)−H complex I, followed by carbonyl-directed substrate coordination to generate intermediate II. This coordination proves crucial for site-selective reactivity, leading to nickel-alkyl species III. To explain the observed chain-walking selectivity, we performed DFT calculations examining the energetics of β-hydride elimination and migratory insertion steps in the Ni-γ to Ni-β transformation (Fig. 7B). Our calculations revealed a high activation barrier (ΔG^‡ = 29.4 kcal/mol) for β-hydride elimination from the Ni-γ intermediate, making this process kinetically unfavorable at room temperature. This computational insight aligns with experimental observations: At elevated temperatures, an equilibrium is established between intermediates In1 and In3, with the thermodynamically favored In3 accumulating through a chain-walking process, enabling regioselective hydrobromination. Although NFTPT is not thermodynamically strong enough to oxidize Br⁻ directly, UV-Vis spectroscopy supports an EDA-triggered pathway that generates Br• at a low, steady-state concentration, inherently controlled by a reversible SET/BET process. Electron paramagnetic resonance spectroscopy further confirms Br• formation through detection of the PBN–Br spin adduct (see the Supplementary Materials for details). This controlled radical generation is crucial to minimize dibromide side products and enables the reaction to proceed via a radical pathway. The low radical concentration directly influences the frequency of productive molecular collisions, making the generation of Br radicals and their subsequent addition to Ni(II) complexes the rate-limiting step of the overall transformation. The key C─Br bond–forming step occurs through oxidation of intermediate III by Br• to form species IV. Rapid Ni─C bond homolysis produces radical intermediate IV′, which undergoes S_H2-type reaction (52, 53) to give the hydrobromination product and Ni(I). The cycle completes with NFTPT oxidation of Ni(I) to nickel tetrafluoroborate, followed by hydrosilane reduction to regenerate the active Ni−H species (54).

Fig. 7. Proposed mechanism.

(A) Proposed reaction pathway for nickel-hydride-catalyzed hydrobromination. (B) Computed Gibbs free energy profiles for selectivity determination. Calculations performed at B3LYP-D3/SDD//B3LYP-D3/6-31G(d,p) level of theory with self-consistent reaction field approach for solvation (ε = 5.9867, ethyl acetate).

Synthetic application

Our methodology provides strategic regiodivergent functionalizations that allow for controlled diversification into multiple distinct regioisomeric products. Starting from common alkenes, our strategy enables this controlled diversification combined with chain-walking hydrobromination as depicted in Fig. 8. The generated β and γ-alkyl bromides were converted into the corresponding products forming C─N and C─S bonds (10a, 10b, 12a, and 12b) (55). In addition, photocatalytic trifluoroacetylation successfully afforded the desired products (11a and 11b) (56). These alkyl bromides can be readily converted into pharmaceutically relevant scaffolds, highlighting their versatility as synthetic building blocks (13a and 13b) (57). Furthermore, the generated alkyl bromides serve as versatile coupling partners, enabling efficient enantioselective transformations (14 and 15) (58).

Fig. 8. Synthetic application: Regiodivergent functionalization from common alkenes.

Reactions were conducted from β and γ-bromoamides. Isolated yields. Ar = 4-(CO₂Me)Ph. (i) NaH, DMF, CH₂Cl_2, 25°C, 1 hour / NaH, tetrahydrofuran, 25°C, 2 hours; (ii) (CF₃CO)₂O, Ir[(dF(Me)ppy)₂dtbbpy]PF₆, Ph₃SiH, K₂HPO₄, 2,6-dimethoxypyridine, MTBE, blue light-emitting diode (LED), 12 hours; (iii) KSCN, MeCN, 80°C, 3 hours; (iv) bisacodyl N-N salt, NaOAc, (TMS)₃SiH, MeCN, blue LED, 24 hours. ^bNiBr₂•DME, Ligand, ZnI₂, Mn, alkyl iodide, 2-methyl-1-propanol, 2-pentanol, 25°C, 24 hours.

DISCUSSION

In summary, we have developed a nickel hydride–catalyzed system for regiocontrolled hydrobromination that addresses key challenges in C(sp³)─Br bond construction through two complementary approaches. The first achieves regioselective direct hydrobromination of both terminal and internal alkenes using an N-fluoropyridinium oxidant system, which enables bromine radical generation and nickel catalyst turnover through a dual-function oxidation process. The second uses temperature-dependent chain-walking to provide regiodivergent access to β- or γ-brominated products from identical alkene precursors with high selectivity. Our mechanistic studies revealed a radical-mediated pathway and established the thermodynamic basis for selective chain-walking processes. The methodology shows broad functional group tolerance and enables late-stage functionalization of pharmaceutical compounds. This unified strategy provides a general platform for accessing diverse alkyl bromide architectures from simple alkenes while offering fundamental insights into selective C─Br bond construction through both direct and chain-walking pathways.

MATERIALS AND METHODS

General procedure for direct hydrobromination

In an argon-filled glove box, to a flame-dried 4-ml vial equipped with a magnetic bar were added Ni(ClO₄)₂•6H₂O (10 mol %, 0.01 mmol, and 3.7 mg) and L1 (12 mol % and 8.5 mg) and anhydrous ⁱPrOAc (0.5 ml). The catalyst solution was stirred for 10 min at room temperature. In the air, to a separate flame-dried 4-ml vial equipped with a magnetic bar was added the alkene 1 (1.0 equiv and 0.1 mmol). The reaction vial was sealed with a polytetrafluoroethylene (PTFE)/silicon septa cap, which was pierced by a 22-gauge needle, and was placed into an argon-filled glove box. In the glove box, LiBr (2.0 equiv, 0.2 mmol, and 17.4 mg) and NFTPT [Ox]-1 (2.0 equiv, 0.2 mmol, and 45.4 mg) were added to a 4-ml vial. The catalyst solution was added to the reaction vial in one portion via syringe. After addition of (MeO)₂MeSiH (3.0 equiv, 0.3 mmol, and 37 μl) and H₂O (1.5 equiv, 0.15 mmol, and 2.7 μl), the reaction vial was sealed with a screw cap and removed from the glove box. The reaction mixture was stirred at 25°C for 18 hours. The resulting mixture was diluted with 1 ml of distilled water and extracted with EtOAc (3 × 1 ml). The combined organic layer was dried over Na₂SO₄. After removal of solvent, the residue was purified by flash column chromatography on silica gel.

General procedure for chain-walking hydrobromination (γ-selectivity)

In an argon-filled glove box, to a flame-dried 4-ml vial equipped with a magnetic bar were added Ni(BF₄)₂•6H₂O (7.5 mol %, 0.0075 mmol, and 2.6 mg) and L1 (9 mol %, 0.009 mmol, and 6.4 mg) and anhydrous ⁱPrOAc (0.5 ml), and the catalyst solution was stirred for 10 min at room temperature. In the air, to a separate flame-dried 4-ml vial equipped with a magnetic bar was added the alkene 1 (1.0 equiv and 0.1 mmol). The reaction vial was sealed with a PTFE/silicon septa cap, which was pierced by a 22-gauge needle, and was placed into an argon-filled glove box. In the glove box, LiBr (2.0 equiv, 0.2 mmol, and 17.4 mg) and NFTPT [Ox]-1 (2.0 equiv, 0.2 mmol, and 45.4 mg) were added to a 4-ml vial. The catalyst solution was added to the reaction vial in one portion via syringe. After addition of (MeO)₂MeSiH (3.0 equiv, 0.3 mmol, and 37 μl), the reaction vial was sealed with a screw cap and removed from the glove box. The reaction mixture was stirred at 20°C for 18 hours. The resulting mixture was diluted with 1 ml of distilled water and extracted with EtOAc (3 × 1 ml)_. The combined organic layer was dried over Na₂SO_4. After removal of solvent, the residue was purified by flash column chromatography on silica gel.

General procedure for chain-walking hydrobromination (β-selectivity)

In an argon-filled glove box, to a flame-dried 4-ml vial equipped with a magnetic bar were added NiBr₂•diglyme (12.5 mol %, 0.0125 mmol, and 4.4 mg) and L2 (15 mol %, 0.015 mmol, and 8.1 mg) and anhydrous ⁱPrOAc (0.5 ml), and the catalyst solution was stirred for 10 min at room temperature. In the air, to a separate flame-dried 4-ml vial equipped with a magnetic bar was added the alkene 1 (1.0 equiv, 0.1 mmol). The reaction vial was sealed with a PTFE/silicon septa cap, which was pierced by a 22-gauge needle, and was placed into an argon-filled glove box. In the glove box, LiBr (1.5 equiv, 0.15 mmol, and 13.0 mg) and NFTPT [Ox]-1 (1.5 equiv, 0.15 mmol, and 34.0 mg) were added to a 4-ml vial. The catalyst solution was added to the reaction vial in one portion via syringe. After the addition of (MeO)₂MeSiH (3.0 equiv, 0.3 mmol, and 37 μl) and H₂O (2.0 equiv, 0.2 mmol, and 3.6 μl), the reaction vial was sealed with a screw cap and removed from the glove box. The reaction mixture was stirred at 80°C for 4 hours. The resulting mixture was diluted with 1 ml of distilled water and extracted with EtOAc (3 × 1 ml)_. The combined organic layer was dried over Na₂SO_4. After removal of solvent, the residue was purified by flash column chromatography on silica gel.

Supplementary Materials

This PDF file includes:

Supplementary Text

Figs. S1 to S13

Tables S1 to S22