NiH-Catalyzed Reductive Hydrocarbonation of Enol Esters and Ethers

Open AccessCCS ChemistryRESEARCH ARTICLE1 Feb 2022NiH-Catalyzed Reductive Hydrocarbonation of Enol Esters and Ethers Xiao-Xu Wang†, Lu Yu†, Xi Lu, Zhi-Lin Zhang, De-Guang Liu, Changlin Tian and Yao Fu Xiao-Xu Wang† Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei 230026 Institute of Energy, Hefei Comprehensive National Science Center, Hefei 230031 , Lu Yu† High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031 , Xi Lu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei 230026 Institute of Energy, Hefei Comprehensive National Science Center, Hefei 230031 , Zhi-Lin Zhang Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei 230026 Institute of Energy, Hefei Comprehensive National Science Center, Hefei 230031 , De-Guang Liu Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei 230026 Institute of Energy, Hefei Comprehensive National Science Center, Hefei 230031 , Changlin Tian High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031 School of Life Sciences, University of Science and Technology of China, Hefei 230027 and Yao Fu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory of Biomass Clean Energy, Center for Excellence in Molecular Synthesis of CAS, University of Science and Technology of China, Hefei 230026 Institute of Energy, Hefei Comprehensive National Science Center, Hefei 230031 https://doi.org/10.31635/ccschem.021.202000760 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Chiral dialkyl carbinols and their derivatives are significant synthetic building blocks in organic chemistry and related fields. The development of convenient and efficient methods to access these compounds has long been an important endeavor. Herein, we report a NiH-catalyzed reductive hydroalkylation and hydroarylation of enol esters and ethers. α-Oxoalkyl organonickel species were generated in situ in a catalytic mode and then participated in cross-coupling with alkyl or aryl halides. This approach enabled C(sp3)–C(sp3) and C(sp3)–C(sp2) bond formation under mild reductive conditions with simple operations, thereby boosting a broad substrate scope and good functional compatibility. Esters of enantioenriched dialkyl carbinols were accessed in a catalytic asymmetric version. Mechanistic studies demonstrated that this reaction proceeded through a syn-addition of Ni–H intermediate to an enol ester with high regio- and enantioselectivity. Download figure Download PowerPoint Introduction Enantiomerically pure alcohols and their derivatives are common synthetic building blocks in organic chemistry and related fields. They are also frequent substructures of natural products and drug molecules (Scheme 1a). For a long time, considerable efforts have been devoted to the development of convenient and efficient methods for the synthesis of these compounds in catalytic asymmetric modes (Scheme 1b).1–6 However, some restrictions remain: The reported suitable substrate scope for the kinetic resolution of racemic alcohols was limiting. For instance, asymmetric hydrogenation of ketones has been widely used in industrial production. Nonetheless, the process barely yielded satisfactory performance in dialkyl ketones, especially when encountered with the generation of dialkyl carbinols that bear two aliphatic substituents in minimally differentiated steric and electronic properties. Until recently, Zhou and co-workers7 achieved considerable progress in asymmetric hydrogenation of dialkyl ketones to access chiral dialkyl carbinols using iridium and bulky phosphine catalyst. The nucleophilic addition of organometallic reagents with carbonyl compounds provides another straightforward route; nevertheless, this reaction focused on simple nucleophiles. Despite these achievements and their associated challenges, alternative methods that utilize mild conditions to access enantiomerically pure alcohol and its derivative have been pursued. Scheme 1 | (a–d) State of the art of asymmetric catalytic synthesis of dialkyl carbinols and Ni–H-initiated reductive hydroalkylation. dtbbpy, 4,4′-di-tert-butyl-2,2′-bipyridine; Boc, tert-butyloxycarbonyl; ee = enantiomeric excess. Download figure Download PowerPoint Transition-metal-catalyzed carbon–carbon bond formation has been developed for a few decades and has become one of the most important processes in organic synthesis chemistry.8–10 Different from aryl coupling reactions using easily accessible and stable arylation reagents (e.g., arylboronic, etc.), there are important issues to be addressed for alkyl coupling reactions, including the accessibility of alkyl coupling reagents and the control of reaction enantioselectivity.11–14 Benefiting from the accessibility of starting olefins and alkyl halides, the Ni–H-initiated alkene reductive hydrogenation-coupling strategy has emerged in the past 5 years as a fascinating alternative to traditional electrophile-nucleophile cross-couplings, which could prevent the necessity of pre-preparing hyperactive organometallic reagents and improve the functional group compatibility (Scheme 1c).15–26 In 2016, our group27,28 established a strategy for carbon–carbon formation, namely, a nonasymmetric version of nickel-catalyzed reductive hydroalkylation and hydroarylation of electronically unbiased alkenes in which unactivated alkenes were used as alkylmetallic equivalents. Concerning reductive hydroalkylation to access more valuable enantioenriched products, early examples focused on the coupling of functionalized halides with general alkenes. G. C. Fu's group29,30, Zhu's group 31, and our group32 independently reported the enantioconvergent reductive hydroalkylation of alkenes with racemic secondary and even more challenging tertiary29 alkyl electrophiles. Recently, we and several other groups became interested in the coupling of functionalized alkenes with unactivated halides, since both pathways could provide analogous products.33,34 To a certain extent, many α-heteroatom (N, O, S, etc.) alkyl halides are challenging to prepare, as functionalized alkenes are readily accessible than their functionalized alkyl halide counterparts.35,36 Most recently, Hu's group, Shu's group, and our group independently demonstrated that the carbon stereocenter could be controlled using achiral enamides37–39 and alkenyl boronates,40 namely hydroalkylation of enamides or alkenyl boronates to produce enantioenriched aliphatic amines or alkyl boronates. In this context, we envisioned that this new strategy might realize the direct catalytic asymmetric synthesis of enantioenriched dialkyl carbinols and their derived esters (Scheme 1d). This approach uses accessible enol esters and alkyl halides to generate enantioenriched dialkyl carbinols via C(sp3)–C(sp3) bond formation under mild reductive conditions with simple operations. This approach is universal and efficient in introducing a broad scope of alkyl substituents at the α-position of chiral alcohol esters, and it exhibits high tolerance to substituents bearing varying functional groups; thus, complementing the existing methods. However, there are still many difficulties in realizing this design.41 Compared with the studies by G. C. Fu et al.,8,11 the chiral center in our reaction was located on a nucleophilic enol ester, which was different from the well-known enantioselectivity control on an alkyl radical generated from the corresponding electrophile pattern. Even the successful asymmetric hydroalkylation of enamides and alkenyl boronates could not be applied directly to enol esters. The electron density of the double bond in alkenyl boronate favored the addition of nickel into the α-position of the boron atom. In comparison, an enol ester had a much more positive electronegativity on α-position [see Supporting Information Section 10, Figures S5–S10 for density functional theory (DFT) calculations], implying that it is a more unfavorable substrate. In cases of enamides and enecarbamates, the carbonyl group coordination facilitates the formation of a stable five-membered nickelacycle, leading to α-selective nickel insertion. However, the oxygen atom in enol ester has a weaker Lewis alkalinity than that in enecarbamate, and thus, a more unfavorable directing group.42 All these vast differences in chemical properties and the negative factors associated with an enol ester hydrometallation would have significant adverse effect on reaction efficiency and enantioselectivity. Experimental Section Experimental methods Reductive hydrocarbonation of enol esters and ethers In the air, NiCl2(PPh3)2 (0.020 mmol, 13.0 mg), dtbbpy (0.030 mmol, 8.0 mg) (dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine), Na2CO3 (0.6 mmol, 64.0 mg), and alkyl halide 2a (0.4 mmol, 125 mg) were added to a Schlenk tube equipped with a stir bar. The Schlenk tube was evacuated and filled with argon (three cycles). To these solids, 1 mL N,N-dimethylformamide (DMF)/H2O (v:v = 1000:1, 0.2 M) was added under an argon atmosphere. Then, diethoxymethylsilane (DEMS) (0.6 mmol, 96 μL) and enol ester 1a (0.2 mmol, 35 mg) were added sequentially under an argon atmosphere. The mixture was stirred at 40 °C for 12 h and purified by column chromatography (silica gel; petroleum ether/ethyl acetate) to afford the desired product 3aa. More experimental details and characterization are available in Supporting Information. Asymmetric reductive hydroalkylation of enol esters In the air, NiCl2(PPh3)2 (0.020 mmol, 13.0 mg), (S,S- L1) (0.030 mmol, 10.0 mg), K3PO4(H2O) (0.4 mmol, 92.0 mg), and alkyl halide 2a (0.2 mmol, 62.5 mg) were added to a Schlenk tube equipped with a stir bar. The Schlenk tube was evacuated and filled with argon (three cycles). To these solids, 2 mL N,N-dimethylacetamide (DMAc)/1,2-dichloroethane (DCE) (v:v = 1:4, 0.1 M) was added under an argon atmosphere and stirred at room temperature for 10 min. Then, (MeO)3SiH (0.6 mmol, 76 μL) and enol ester 1n (0.4 mmol, 94.0 mg) were added sequentially under an argon atmosphere. The mixture was stirred at 5 °C for 36 h and purified by column chromatography (silica gel; petroleum ether/ethyl acetate) to afford the desired product 3na. More experimental details and characterization are available in Supporting Information. Computational methods All calculations were performed using Gaussian 16, Rev. C01. The DFT functional of B3LYP, associated with the Grimme empirical dispersion correction (GD3BJ), was used to optimize all intermediates and transition states' geometry. The def2SVP basis set was employed on all elements. The solvent effects were taken into account in all calculations using the solvation model based on solute electron density (SMD) with 1,2-dichloroethane (CH2ClCH2Cl). Results and Discussion Reaction development We began this study with the synthesis of ester 3aa through the reductive hydroalkylation of enol ester 1a with alkyl iodide 2a (Table 1). We determined that this reaction was proceeded efficiently using a nickel/bipyridine/triphenylphosphine catalyst with DEMS and Na2CO3 in a DMF/H2O mixed solvent (entry 1), and the impact of each reaction parameter on the coupling efficiency was summarized. Bidentate N-ligands gave adequate to good productivity, except the sterically hindered ligand bearing two ortho-methyl groups. The tridentate N-ligands were tested with trace amounts of the desired products. Triphenylphosphine, in our catalytic system, had a positive effect due to its weak coordination ability (entry 2); it could stabilize the Ni catalyst and de-coordinate from the Ni center to generate accessible reaction site.43 In 31P NMR studies, we observed that triphenylphosphine would dissociate from the catalyst and react with water to form triphenylphosphine oxide (see Supporting Information Section 8.4 for more details). Besides, we showed that the addition of excess triphenylphosphine to NiBr2(diglyme) (diglyme = 2-methoxyethyl ether) would significantly improve the yield from 34% to 71% (entry 3). Nitrogen and phosphine dual ligand effects were also observed in previous works from Weix et al.,44 Wang et al.,45,46 and our group,28 respectively. Other nickel salts could also be used, which led to varying degrees of reduced yields (entry 2), but the reaction did not take place without the addition of nickel catalysts or using other transition-metal (e.g., Pd, Fe, Co, or Cu) catalysts (entries 4 and 5). Similar to our previous studies,27,28,32 we confirmed that the cross-combination of different bases and silanes significantly regulated the reaction activity (entries 6–10). In general, an oxygen-bearing silane combined with a weak to moderate base could yield satisfactory results. This reaction is not highly dependent on solvents (entries 11–13); good yields could be obtained in common high-polarity solvents [e.g., 1-methyl-2-pyrrolidinone (NMP), DMAc, and CH3CN], while low yields were obtained using lower-polarity solvents [e.g., DCE, tetrahydrofuran (THF), iPr2O, and 1,4-dioxane]. Finally, a microscale amount of water played a positive role in promoting this reaction (entry 14), and a lower temperature shut down the reaction (entries 15–17). Table 1 | Optimization of the Reaction Conditions for NiH-Catalyzed Reductive Hydrocarbonationa Entry Deviation from the Standard Conditions Yield (%) 1 None 94 ( 90b) 2 NiBr2(diglyme), NiI2(xH2O), Ni(OTf)2, or NiCl2(dppp) instead of NiCl2(PPh3)2 34–47 3 NiBr2(diglyme) + 10% PPh3 instead of NiCl2(PPh3)2 71 4 Without NiCl2(PPh3)2 N.R. 5 PdCl2(PPh3)2, FeI2, CoBr2(DME), or CuI instead of NiCl2(PPh3)2 N.R. 6 Ph2SiH2, DMMS, (MeO)3SiH, or PMHS instead of DEMS 61–85 7 MeEt2SiH instead of DEMS 10 8 K3PO4(H2O), KHCO3, or NaHCO3 instead of Na2CO3 73–77 9 NaF or CsF instead of Na2CO3 19–33 10 Mg(OAc)2(4H2O) instead of Na2CO3 <5 11 NMP, DMAc, or CH3CN instead of DMF 61–86 12 DCE, THF, or iPr2O instead of DMF 6–9 13 1,4-dioxane instead of DMF <5 14 moisture content 100:1, 500:1, or 2000:1 instead of 1000:1 88–92 15 0 °C <5 16 20 °C 62 17 60 °C 78 Note: Tf, triflyl; Ac, acetyl; dppp, 1,3-bis(diphenylphosphino)propane; DME, 1,2-dimethoxyethane; diglyme = 2-methoxyethyl ether; NMP, 1-methyl-2-pyrrolidinone; DMAc, N,N-dimethylacetamide; DMF, N,N-dimethylformamide; DCE, 1,2-dichloroethane; THF, tetrahydrofuran; DMMS, methyldimethoxysilane; DEMS, diethoxymethylsilane; PMHS, polymethylhydrosiloxane; N.R., no reaction. aConditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.2 mmol, 2.0 equiv), nickel catalyst (0.01 mmol, 10 mol %), ligand (0.015 mmol, 15 mol %), silane (0.3 mmol, 3.0 equiv), base (0.3 mmol, 3.0 equiv), solvent (0.5 mL, 0.2 M), 12 h. Bis(4-methoxyphenyl)methanone was used as an internal standard. Gas chromatography (GC) yield. bIsolated yield in parentheses. Scope of the racemic reaction Having established optimal reaction conditions, we investigated the substrate scope of this reductive hydrocarbonation process. As shown in Table 2, a wide range of alkyl halide coupling partners was examined, including both alkyl iodides and bromides (with NaI as an additive) that furnished gratifying results in all cases. A variety of synthetic valuable functional groups were well accommodated, including relatively robust ether ( 3aa, 3ad, and 3ae), ester ( 3af and 3ag), trifluoromethyl ( 3ag), and cyano ( 3ah and 3ai) groups. Benefiting from the mild reaction conditions, base-sensitive ketones ( 3aj and 3ak), an easily reduced aldehyde group ( 3al), and an amide-possessing an N–H bond ( 3am) were compatible during the transformation. Notably, aryl chloride ( 3an), alkyl chloride ( 3ao), and aryl bromide ( 3ap) survived, indicating good chemoselectivity of this reaction. These surviving electrophilic sites provided the possibility for further manipulations. Heterocyclic compounds such as morpholine ( 3aq), thiophene ( 3ar), furan ( 3as), indole ( 3at), and coumarin ( 3au) moieties also posed no problems. In the design of medicine candidates, methylation is commonly used to improve biological activities and physical properties. Thus, we were delighted that iodomethane and its perdeuterated form were indeed suitable substrates and afforded the corresponding methylation products ( 3av and 3aw). The optimal reaction conditions could be extended to reductive hydroarylation ( 5aa and 5ab) when using aryl iodides as the coupling partner. A limitation of this reaction is the failure to couple secondary alkyl halides with significant dehalogenation and still required further optimization of reaction conditions. Also, the scope of enol esters and ethers was fairly broad, and single α-alkylation regioselectivity was observed in all cases. Both the protecting groups and the alkyl substituents in enol esters could range in their steric and electronic properties. For example, less steric acetyl ( 3ba– 3ea), sterically hindered benzoyl ( 3fa), and easily removed tert-butyloxycarbonyl ( 3ga) could be present. Both acyclic ( 3ha) and cyclic ( 3ia) enol ethers could be converted; the cyclic species ( 3ia) exhibited a higher reactivity. Various functional groups such as furan ( 3ja), phthalimide ( 3ka), and internal alkene ( 3la) were exceptionally compatible. The tolerance of sensitive functional groups ( 3al and 3az) demonstrated that this reaction offers appealing advantages over the previous nucleophilic addition of organometallic reagents with carbonyl compounds. Further, we tested the coupling of silyl enol ether; however, we did not observe an appreciable desired product; instead, a large proportion of the starting material, silyl enol ether, was recovered. Finally, due to the mild reaction conditions, this reaction found applications in the late-stage modification of complex bioactive molecules, exhibiting strong potential in the functionalization of glucose ( 3ax), indomethacin ( 3ay), and lithocholic acid ( 3az). Table 2 | Scope of the Racemic NiH-Catalyzed Reductive Hydrocarbonation Reactiona aStandard conditions for the racemic reaction: enol ester or ether (0.2 mmol, 1.0 equiv), alkyl or aryl halide (0.4 mmol, 2.0 equiv), NiCl2(PPh3)2 (0.02 mmol, 10 mol %), dtbbpy (0.03 mmol, 15 mol %), DEMS (0.6 mmol, 3.0 equiv), Na2CO3 (0.6 mmol, 3.0 equiv), DMF/H2O (1.0 mL, v/v = 1000:1), 40 °C, 12 h, isolated yield. bNaI (0.2 mmol, 1.0 equiv) as an additive. cDiastereocenters marked with a spherical symbol. dr, diastereomeric ratio. Scope of the asymmetric reaction Next, we determined that asymmetric reductive hydroalkylation to synthesize esters of dialkyl carbinols could be realized using a chiral nickel/bisoxazoline ( L1)/triphenylphosphine catalyst with trimethoxysilane and K3PO4(H2O) in a DMAc/DCE mixed solvent (see Supporting Information Section 3 for more details). Although the vital role of water is unclear in this reaction, it is indeed a decisive component for the enantioselectivity. Two equivalents of K3PO4(H2O) as a base provided the appropriate amount of water to obtain high enantioselectivity. The results of the scoping study of this asymmetric variant are summarized in Table 3. Various of tert-butyloxycarbonyl-protected enols and alkyl iodides were smoothly coupled to deliver the desired products in moderate isolated yields (30–52% yield) with uniformly high enantioinduction [88–97% enantiomeric excess (ee)]. Besides, the Z/E configuration of the enol ester would not affect the coupling efficiency and enantioselectivity. This asymmetric reductive hydroalkylation progressed under mild conditions, and thus, tolerated a broad range of functional groups such as those of ether ( 3na, 3nd, 3ge, and 3ra), trifluoromethyl ( 3nA), acetyl ( 3nC), cyano ( 3nh), and tert-butyloxycarbonyl protected secondary arylamine ( 3nm). Moreover, an electrophilic alkyl tosylate ( 3oD) and an aryl chloride ( 3sa) survived in the reaction, being converted readily by further functionalization reactions. Notably, the asymmetric reaction conditions were not suitable for hydroarylation. Fortunately, the corresponding chiral benzyl alcohols were easy to access through well-developed asymmetric hydrogenation strategies.47,48 The feasibility of constructing an enantioenriched dialkyl carbinol center bearing two aliphatic substituents with minimally differentiated steric and electronic properties demonstrated that this reaction could supplement long-standing methods, including the kinetic resolution of racemic alcohols and asymmetric hydrogenation of ketones (see Supporting Information Figures S3 and S4 and Tables S1–S5 for assignment of absolute configuration of 3na). Table 3 | Scope of the Asymmetric NiH-Catalyzed Reductive Hydroalkylation Reactiona aStandard conditions for asymmetric reaction: enol ester (0.4 mmol, 2.0 equiv), alkyl iodide (0.2 mmol, 1.0 equiv), NiCl2(PPh3)2 (0.02 mmol, 10 mol %), (S,S)- L1 (0.03 mmol, 15 mol %), (MeO)3SiH (0.6 mmol, 3.0 equiv), K3PO4(H2O) (0.4 mmol, 2.0 equiv), DMAc/DCE (2.0 mL, v/v = 1:4), 5 °C, 36 h, isolated yield. Ts, tosyl. Mechanistic studies Finally, we investigated the reaction mechanism of the NiH-catalyzed reductive hydrocarbonation through several conventional experiments (Scheme 2). In the radical clock experiment (Scheme 2a) with 5-iodopent-1-ene ( 2E), the assumed products 3aE′ and 3aE″ were not observed, but linear coupling products ( 3aE) were produced with the migration of alkenyl double bond. We also tested the reaction of an alkyl bromide ( 2F) containing a cyclopropyl ring. We obtained the ring-opened product ( 3aF) with a 63% isolated yield, but the assumed terminal double bond migrated. From the above results, we concluded that a radical pathway was involved in the activation of alkyl halides, and the migration of the alkenyl double bond was a considerably fast step. Next, we carried out deuterium-labeling experiments to study the stereochemistry of this reductive hydrocarbonation (Scheme 2b). Deuterated hydrosilane (Ph2SiD2) was used instead of DEMS under the standard reaction conditions. We observed that deuterium incorporation at the β-position of the acyloxy group, and no H/D exchange was noted at both α- and γ- positions of the acyloxy group, which indicated that the insertion of Ni–H across the double bond of enol ester was highly regioselective and irreversible. The matched high Z/E ratio of enol ester ( 1n) and high diastereoselectivity of deuterated products (d1- 3nv and d1- 3nv′) indicated that enol ester Z/E isomerization did not occur. In addition, a fast equilibrium formation of a pair of a low-valent nickel species and an oxoalkyl radical by homolysis of the Ni–C bond could also be excluded.49,50 Collectively, these stereochemical results revealed that this reaction proceeded through a syn-addition of Ni–H intermediate to an enol ester to generate an α-oxoalkyl organonickel species with high regioselectivity and diastereoselectivity. Next, we performed a low-temperature (10 K) X-band electron paramagnetic resonance (EPR) experiment to analyze the reaction mixture after different reaction times.51–53 The experimental EPR spectrum (top four lines) and corresponding simulation spectra (bottom two lines) are shown in Scheme 2c (see Supporting Information Figure S2 for more details). At the initial state (1 min), the reaction produced an EPR spectrum typical of a low-spin signal with g values at 2.27 and 2.02, implying that the Ni(II) catalyst complex was reduced to Ni(I) state. As the reaction proceeded, the EPR signal corresponding to Ni(I) vanished and the signal of Ni(III) appeared as peaks at g = 2.20 and 1.99. The amplitude of Ni(III) reached a maximum after about 1 h and gradually decreased. At the end of the reaction (420 min), no EPR signal was observed, indicating that all the Ni returned to +2 valence state, which was "EPR-silent" at X-band. Moreover, we performed an EPR spin-trapping experiment and characterized radical intermediates after different reaction times (Scheme 2d) (see Supporting Information Figure S1 for more details). The experimental EPR spectrum in the presence of spin trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO) after (1) 30 min and (3) 60 min of reaction and the simulation of the measured signal at (2) 30 min and (4) 60 min are shown. Both EPR spectrum (1) and (3) could be satisfactorily simulated with three radical components, including (5) DMPO-H, aN = 14.77 G, aH = 19.90 G (2 β-H atoms); (6) DMPO-R1, aN = 14.57 G, aH = 17.63 G; and (7) DMPO-R2, aN = 14.53 G, aH = 20.76 G. Besides, the EPR spectrum collected at 30 min could be simulated with the three radical components in the following ratio: DMPO-R1:DMPO-R2:DMPO-H = 0.2:0.7:0.1, while EPR spectrum collected at 60 min could be simulated with the three radical components in the following ratio: DMPO-R1:DMPO-R2:DMPO-H = 0.39:0.47:0.14. Note that oxoalkyl radical could be observed when spin trapping agent (DMPO) was added, likely caused by a competitive reaction pathway that destroyed the fast reductive elimination step.54–57 Although we obtained some convincing experimental data, it is still difficult to clearly understand the reaction mechanism. In particular, we could not clarify the fundamentals of the change in valence states of nickel during the reaction process. With the help of existing literature,16,29,32,51,58,59 we proposed the presumptive mechanism for the reductive hydroalkylation process as a radical-chain pathway (left, Scheme 2e), as follows: First, a ligand-bound nickel(I) species ( A) was generated as the active catalyst under the reductive conditions, which could react with an alkyl halide to afford an alkyl radical and nickel(II) salt ( B). Second, the resultant nickel(II) salt ( B) reacted with the hydrosilane and formed a nickel(II) hydride ( C). Then the nickel(II) hydride ( C) was incorporated into the enol ester to generate an α-oxoalkyl organonickel(II) species ( D). Third, recombination of the alkyl radical afforded a Ni(III) intermediate ( E). This Ni(III) intermediate ( E) underwent fast reductive elimination to deliver the desired hydroalkylation product and regenerated the active Ni(I) species ( A), thereby closing the catalytic cycle. The enantioselectivity-controlling step was proved to be the syn-addition of Ni–H intermediate with high regio- and enantioselectivity, different from previous related studies.29,31,60,61 The proposed mechanism for reductive hydroarylation is also shown in Scheme 2e (right). Also, this mechanistic variant was proposed by many other groups.33,34 First of all, a ligand-bound nickel(I) species ( A′) formed from the reduction of the initial catalyst. The resulting A′ reacted with hydrosilane to produce nickel(I) hydride species ( B′). Nickel(I) hydride B′ was inserted into the enol ester and generated an α-oxoalkyl organonickel species ( C′). Subsequent oxidative addition of aryl halide afforded a Ni(III) intermediate ( D′), which underwent reductive elimination to deliver the desired hydroarylation product and Ni(I) species to finish the cross-coupling. Scheme 2 | (a–e) Preliminary mechanistic studies of the NiH-catalyzed reductive hydrocarbonation of enol esters and ethers. Download figure Download PowerPoint Conclusion We describe a NiH-catalyzed reductive hydroalkylation and hydroarylation of enol esters and ethers. This convenient method employed accessible alkyl and aryl halides as user-friendly alkylation or aryla