•Novel strategy for enantioselective remote hydrofunctionalization•Two simple ligands are better than a complex one: simplification of chiral ligand design•Formal remote asymmetric C(sp3)–H arylation•Practical, mild, and scalable process, excellent regio- and enantioselectivities Selective functionalization of remote aliphatic C–H bonds in a regio- and enantioselective fashion is a synthetically valuable but challenging process. Enantioselective NiH-catalyzed remote hydrofunctionalization is such an ideal process to construct complex molecules from easily accessed olefinic substrates. However, the traditional single-ligand catalytic strategy requires the single chiral ligand used to efficiently promote both chain-walking and asymmetric coupling steps, which makes it difficult for chiral ligand design. In this paper, we demonstrate that the synergistic combination of an achiral chain-walking ligand and a chiral asymmetric cross-coupling ligand offers a novel and general solution. It is anticipated that this relay catalysis (L/L∗) strategy could inspire the development of organometallic multistep relay catalysis process, as well as asymmetric transformations. Ligand-controlled reactivity plays an important role in transition-metal catalysis, enabling a vast number of efficient transformations to be discovered and developed. However, a single ligand is generally used to promote all steps of the catalytic cycle (e.g., oxidative addition, reductive elimination), a requirement that makes ligand design challenging and limits its generality, especially in relay asymmetric transformations. We hypothesized that multiple ligands with a metal center might be used to sequentially promote multiple catalytic steps, thereby combining complementary catalytic reactivities through a simple combination of simple ligands. With this relay catalysis strategy (L/L∗), we report here the first highly regio- and enantioselective remote hydroarylation process. By synergistic combination of a known chain-walking ligand and a simple asymmetric cross-coupling ligand with the nickel catalyst, enantioenriched α-aryl alkylboronates could be rapidly obtained as versatile synthetic intermediates through this formal asymmetric remote C(sp3)-H arylation process. Ligand-controlled reactivity plays an important role in transition-metal catalysis, enabling a vast number of efficient transformations to be discovered and developed. However, a single ligand is generally used to promote all steps of the catalytic cycle (e.g., oxidative addition, reductive elimination), a requirement that makes ligand design challenging and limits its generality, especially in relay asymmetric transformations. We hypothesized that multiple ligands with a metal center might be used to sequentially promote multiple catalytic steps, thereby combining complementary catalytic reactivities through a simple combination of simple ligands. With this relay catalysis strategy (L/L∗), we report here the first highly regio- and enantioselective remote hydroarylation process. By synergistic combination of a known chain-walking ligand and a simple asymmetric cross-coupling ligand with the nickel catalyst, enantioenriched α-aryl alkylboronates could be rapidly obtained as versatile synthetic intermediates through this formal asymmetric remote C(sp3)-H arylation process. IntroductionOrganic synthesis has been revolutionized over the past half-century by the emergence of transition-metal catalysis. Many highly selective and efficient coupling reactions and privileged ligands have been reported by using mono- or multimetallic catalysis (Figure 1A).1de Meijere A. Bräse S. Oestreich M. Metal-Catalyzed Cross-Coupling Reactions and More. 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This requirement makes chiral ligand design especially challenging and results in no successful precedent for enantioselective reductive remote hydrofunctionalization with excellent levels of both regio- and enantioselectivities in NiH chemistry (Figure 1B). To overcome this issue, we envisaged a general, modular solution to this catalysis and an asymmetric relay process that could be realized with two ligands (L/L∗) through a relay catalysis strategy (Figure 1C). Firstly, each ligand should only promote one phase of the catalytic cycle. Ideally, an achiral ligand promotes only chain-walking, and a chiral ligand promotes only cross-coupling. Secondly, two ligands should easily undergo ligand exchange with the nickel catalyst. Lastly, this approach would be especially powerful if libraries of known, structurally simple ligands could be used directly for combinatorial screening. 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We found that a simple combination of an achiral ligand (L) (from a chain-walking ligand library) and a chiral amino alcohol ligand ((S)-L∗) (from a nickel-catalyzed asymmetric cross-coupling ligand library) afforded the desired migratory arylation product (3a) in a 70% isolated yield and 93% enantiomeric excess (ee) as a single regioisomer. (Figure 2, entry 1). Use of a different nickel source, NiBr2·dme led to a somewhat lower yield and ee (Figure 2, entry 2). Both of the ligands are necessary to achieve high regio- and enantioselectivity (Figure 2, entries 3 and 4). The amount of chiral ligand ((S)-L∗) could be reduced to 1 mol % at 5 mmol scale, although slightly diminished yield and ee were obtained (Figure 2, entries 5 and 6), demonstrating the high efficiency of the chiral ligand ((S)-L∗). Various achiral ligands used for chain-walking were less effective (Figure 2, entries 7 and 8), and inferior results were found with other chiral ligands used for asymmetric cross-coupling (Figure 2, entries 9–11). Evaluation of other silanes showed that polymethylhydrosiloxane (PMHS) resulted in a slightly diminished yield and enantioselectivity (Figure 2, entry 12). It was shown that the base KF was necessary for the reaction to proceed (Figure 2, entry 13). The yield could be improved by the addition of LiI as an additive to suppress the reduction of both starting materials (Figure 2, entry 14; see also Table S3), and replacement of the solvent N,N-dimethylacetamide (DMA) with tetrahydrofuran (THF) led to significantly lower yields and decreased ee (Figure 2, entry 15). The more reactive aryl iodide was also a suitable coupling partner and resulted in comparable yield and ee (Figure 2, entry 16). Equivalent yield and enantioselectivity were obtained when homoallyl boronic acid pinacol ester was used as the alkene component (Figure 2, entry 17).Figure 2Variation of reaction parametersShow full captionYields were determined by GC using n-dodecane as the internal standard. The yield in parentheses is the isolated yield and is an average of two runs (0.2 mmol scale). rr refers to regioisomeric ratio, representing the ratio of the major product to the sum of all other isomers as determined by GC and GC-MS analysis. ee refers to enantiomeric excess and was determined by HPLC analysis of the corresponding alcohol after stereospecific oxidation of the boronic ester.a8 mol % single ligand was used. bReaction at 5 mmol scale. iBu, iso-butyl; tBu, tert-butyl; Bdmpd, 2,4-dimethylpentane-2,4-diol boronic ester; Bpin, pinacol boronic ester; DEMS, diethoxymethylsilane; PMHS, polymethylhydrosiloxane; THF, tetrahydrofuran; DMA, N,N-dimethylacetamide.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Substrate scopeWith the optimized conditions in hand, the scope and generality of this remote hydroarylation process was explored and was found to be remarkably broad. As shown in Figure 3A, both unactivated terminal (1a–1f, 1k, 1l) and internal (1g–1j) boron-containing alkenes successfully underwent migratory hydroarylation to produce the desired α-aryl alkylboronates in moderate to good yields and with excellent regio- and enantioselectivity. In 1f, this relay asymmetric catalysis was insensitive to the chain length (the distance from the alkene to the boron) and high regio- and enantioselectivity were still observed. Both unactivated aliphatic E and Z alkenes, as well as E/Z mixtures could produce the corresponding enantiomerically enriched α-aryl alkylboronates smoothly, regardless of the E/Z ratio or position of the C=C double bond in the starting compound. Remarkably, in an alkene substrate with a heteroatomic substituent at the other terminus of the alkyl chain (for example, an ether in 1i), migration toward the boronate group and subsequent α-arylation was still preferred. Of particular relevance was the alkene substrate with an ester substituent at the other terminus of the alkyl chain (1j), in which enantioselective arylation still occurred preferentially at the boronic ester-adjacent C(sp3)–H bond rather than at the ester-adjacent C(sp3)–H bond. Other boronates such as Bpin (pinacol boronic ester) (1d, 1i, 1k) and Bmpd (2-methylpentane-2,4-diol boronic ester) (1l) were also compatible.Figure 3Scope of enantioselective Ni-catalyzed remote hydroarylation of boron-containing alkenesShow full captionUnder each product is the percent yield, enantiomeric excess (ee), and regioisomeric ratio (rr). Yield refers to the isolated yield of the purified product (0.20 mmol scale, average of two experiments). ee determined by HPLC analysis of the corresponding alcohol after stereospecific oxidation of the boronic ester. rr represents the ratio of the major product to the sum of all other isomers as determined by GC and GC-MS analysis.a4-Bromobenzotrifluoride was used. bThe ee value was determined without derivatization. cIsolated as the corresponding alcohol. dAryl iodide was used. eNiBr2∙dme was used. nNon, n-nonyl; nPent, n-pentyl; Bmpd, 2-methylpentane-2,4-diol boronic ester; TBS, tert-butyldimethylsilyl; Tf, triflyl.View Large Image Figure ViewerDownload Hi-res image Download (PPT)A wide array of electronic and sterically differentiated substituted aryl- and heteroaryl groups could be introduced with a corresponding aryl and heteroar