A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral ?-aryl alkylboronates

•Novel strategy for enantioselective remote hydrofunctionalization•Two simple ligands are better than a complex one: simplification of chiral ligand design•Formal asymmetric C(sp3)–H arylation•Practical, mild, and scalable process, excellent regio- enantioselectivities Selective functionalization aliphatic C–H bonds in fashion is synthetically valuable but challenging process. Enantioselective NiH-catalyzed hydrofunctionalization such an ideal process to construct molecules from easily accessed olefinic substrates. However, the traditional single-ligand catalytic requires single used efficiently promote both chain-walking coupling steps, which makes it difficult design. In this paper, we demonstrate that synergistic combination achiral cross-coupling offers novel general solution. It anticipated relay catalysis (L/L?) could inspire development organometallic multistep as well transformations. Ligand-controlled reactivity plays important role transition-metal catalysis, enabling vast number efficient transformations be discovered developed. generally all steps cycle (e.g., oxidative addition, reductive elimination), requirement design limits its generality, especially We hypothesized multiple with metal center might sequentially thereby combining complementary reactivities through ligands. With (L/L?), report here first highly hydroarylation By known nickel catalyst, enantioenriched ?-aryl alkylboronates rapidly obtained versatile synthetic intermediates formal C(sp3)-H arylation IntroductionOrganic synthesis has been revolutionized over past half-century by emergence catalysis. Many selective reactions privileged have reported using mono- or multimetallic (Figure 1A).1de Meijere A. Bräse S. Oestreich M. Metal-Catalyzed Cross-Coupling Reactions More. 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Catalyst-controlled 1,2- 1,1-arylboration ?-alkyl arenes.Angew. 1719-1723Crossref 73Wang Ding olefins.Nat. 951-958Crossref These compounds intermediates, C–B moiety variety stereospecific produce other molecules.ResultsReaction optimizationTo test hypothesis, began investigation system homoallyl acid ester (1a) methyl 4-bromobenzoate (2a) 2; Tables S8–S10). found (L) (from library) amino alcohol ((S)-L?) afforded desired product (3a) 70% isolated yield 93% enantiomeric excess (ee) regioisomer. 2, entry 1). Use source, NiBr2·dme led somewhat lower ee 2). Both necessary high enantioselectivity entries 3 4). amount reduced 1 mol % 5 mmol scale, slightly diminished were 6), demonstrating efficiency ((S)-L?). Various less effective 7 8), inferior 9–11). Evaluation silanes showed polymethylhydrosiloxane (PMHS) resulted 12). shown base KF proceed 13). improved addition LiI additive suppress reduction starting materials 14; Table S3), replacement solvent N,N-dimethylacetamide (DMA) tetrahydrofuran (THF) significantly yields decreased 15). iodide partner comparable 16). Equivalent when pinacol 17).Figure 2Variation parametersShow full captionYields determined GC n-dodecane internal standard. parentheses average runs (0.2 scale). rr refers regioisomeric ratio, representing ratio major sum isomers GC-MS analysis. HPLC analysis corresponding after ester.a8 used. bReaction scale. iBu, iso-butyl; tBu, tert-butyl; Bdmpd, 2,4-dimethylpentane-2,4-diol ester; Bpin, DEMS, diethoxymethylsilane; PMHS, polymethylhydrosiloxane; THF, tetrahydrofuran; DMA, N,N-dimethylacetamide.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Substrate scopeWith optimized conditions hand, generality explored remarkably broad. As 3A, terminal (1a–1f, 1k, 1l) (1g–1j) successfully underwent moderate good enantioselectivity. 1f, insensitive length (the distance boron) still observed. E Z alkenes, E/Z mixtures enantiomerically enriched smoothly, regardless position C=C double compound. Remarkably, heteroatomic substituent terminus (for ether 1i), migration toward boronate group subsequent ?-arylation preferred. Of particular relevance (1j), occurred preferentially ester-adjacent bond. Other Bpin (pinacol ester) (1d, 1i, 1k) Bmpd (2-methylpentane-2,4-diol (1l) compatible.Figure 3Scope alkenesShow captionUnder percent yield, (ee), (rr). Yield purified (0.20 experiments). ester. represents analysis.a4-Bromobenzotrifluoride bThe value without derivatization. cIsolated alcohol. dAryl eNiBr2?dme nNon, n-nonyl; nPent, n-pentyl; Bmpd, 2-methylpentane-2,4-diol TBS, tert-butyldimethylsilyl; Tf, triflyl.View (PPT)A wide array sterically differentiated substituted aryl- heteroaryl groups introduced heteroar