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Nickel-Catalysed Migratory Hydroalkynylation And ARTICLE https://doi.org/10.1038/s41467-021-24094-9 OPEN Nickel-catalysed migratory hydroalkynylation and enantioselective hydroalkynylation of olefins with bromoalkynes ✉ ✉ Xiaoli Jiang1, Bo Han1, Yuhang Xue1, Mei Duan1, Zhuofan Gui1, You Wang 1 & Shaolin Zhu 1 α-Chiral alkyne is a key structural element of many bioactive compounds, chemical probes, and functional materials, and is a valuable synthon in organic synthesis. Here we report a 1234567890():,; NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that delivers the corresponding benzylic alkynylation products in high yields with excellent regioselectivities. Catalytic enantioselective hydroalkynylation of styrenes has also been realized using a simple chiral PyrOx ligand. The obtained enantioenriched benzylic alkynes are versatile synthetic intermediates and can be readily transformed into synthetically useful chiral synthons. 1 State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center ✉ (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2021) 12:3792 | https://doi.org/10.1038/s41467-021-24094-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24094-9 s a key structural element, chiral alkynes motifs bearing sp3-hybridized carbons could undergo versatile transformations an α stereocentre are often found in many bioactive to deliver useful sp2-orsp3-hybridized carbons1. As a result, A 3 – compounds, chemical probes, and functional materials efficient strategies for catalytic, enantioselective C(sp ) C(sp) (Fig. 1a). In addition, they are also valuable synthons as the coupling to generate such stereocentres have long been sought a Representative bioactive molecules bearing a chiral alkyne motif O Chiral alkynes: CF3 Cl chemical probe O CO2H versatile synthons N O bioactive molecules CF3 H AMG 837 Efavirenz (a GPR40 agonist for type 2 diabetes) (anti HIV) b Common strategies for C(sp3 Cu-asymmetric 3 Sonogashira C(sp X H Ni-asymmetric alkylhalide sp-sp3 coupling alkane + + H R X R terminal alkyne alkynyl partner R R' enantioenriched R' alkynes alkene alkene (this work) + + X R alkene alkene (remote) X R alkynyl partner difunctionalization hydroalkynylation alkynyl partner c This work: chemo- & stereoselective NiH-catalysed (migratory) hydroalkynylation of alkenes i NiH-catalysed migratory hydroalkynylation Ar ()n Ar Br + NiH () H R n chemo- & stereo- migratory R unrefined alkene bromoalkyne selective hydroalkynylation I reductive LNi H (alkene over alkyne) insertion elimination NiI ()n Ar ()n Ar () Ar n NiIII chain- NiI oxidative Br walking addition H R chemo- & regioselective avoid organometallic reagents mild & broad scope ii Enantioselective NiH-catalysed hydroalkynylation of vinylarenes Ar Ar + Br R NiH R (S)-PyrOx styrene bromoalkyne enantioenriched alkyne L*NiIH syn-hydrometallation reductive elimination H Ar Br Ar Br Ar R NiIIIL* NiIIIL* Br + NiIL* R R + oxidative addition H fast homolysis Ar Br Ar NiIIL* I Ni L* + alkylnickel generated in situ R Fig. 1 Ni(I)H-catalyzed migratory hydroalkynylation and enantioselective hydroalkynylation. a Representative bioactive molecules bearing a chiral alkyne motif. b Common strategies for C(sp3)–C(sp) coupling. c Chemo- & stereoselective NiH-catalyzed (migratory) hydroalkynylation of alkenes. 2 NATURE COMMUNICATIONS | (2021) 12:3792 | https://doi.org/10.1038/s41467-021-24094-9 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24094-9 ARTICLE (Fig. 1b). For example, Liu2,3 reported an elegant work on Cu- C(sp) cross-coupling partner which is potentially reactive toward catalyzed asymmetric Sonogashira C(sp3)–C(sp) coupling4,5. Shi6 NiH, could be used to achieve remote hydroalkynylation (Fig. 1c, i). and Liu7 have demonstrated that Pd- and Cu-catalyzed C(sp3)–H Successful implementation of this transformation will require (i) a alkynylation could be achieved in an enantioselective fashion. hydrometalation process that can discriminate between alkene Liu8 has also used an alkene difunctionalization strategy to pro- and alkyne and (ii) an alkynylation process highly selective for one duce enantioenriched alkynylation product under copper of the alkylnickel species. A chiral alkyne bearing an α-aryl-sub- catalyst9. Suginome10 has reported a pioneering work on Ni- stituted stereogenic C(sp3)center2–5,7–10,67,68 would be ultimately catalyzed asymmetric hydroalkynylation of 1,3-dienes based on obtained from styrene through hydronickellation and subsequent their previous hydroalkynylation works11,12. As a continued enantioconvergent52,53,55,56,69 alkynylation (Fig. 1c, ii). Here, we development of general alternatives for asymmetric C(sp3)–C(sp) show the successful execution of this reaction. coupling, here we report an appealing approach via metal- hydride13–15 catalyzed asymmetric (remote) hydroalkynylation16 from readily available alkene starting materials. Results Owing to its low-cost, facile oxidative addition, and availability Reaction design and optimization. Our initial studies involved of diverse oxidation states, nickel17,18 has emerged as a catalyst the migratory hydroalkynylation of 4-phenyl-1-butene (1a) using complementary to palladium over the past two decades, especially 1-bromo-2-(triisopropylsilyl)acetylene (2a) as an alkynylation 3 in cross-coupling reaction involving C(sp ) fragments. Reductive reagent (Fig. 2). It was determined that NiI2·xH2O and the migratory hydrofunctionalization19–22 catalyzed by nickel – bathocuproine ligand (L) could generate the desired migratory hydride23 25 has recently been recognized as an alternative pro- alkynylation product as a single regioisomer [rr (benzylic pro- tocol for selective functionalization of remote C(sp3)–H duct: all other isomers) > 99:1] in 82% yield (entry 1). Other 26–66 bonds . Compared to conventional cross-coupling, this pro- nickel sources such as NiBr2 led to lower yields and a moderate rr cess (i) employs readily available, bench-stable alkenes or alkene (entry 2). Ligand screening revealed that the previously used precursors instead of specially generated organometallic reagents ligand29, 6,6′-dimethyl-2,2′-bipyridine (L1) resulted in sig- as starting materials and (ii) could also selectively functionalize a nificantly lower yield and rr (entry 3) while a similar ligand remote C(sp3)–H site in addition to the conventional ipso-posi- neocuproine (L2) led to a similar regioselectivity but a lower yield tion. Since its conception, significant progress has been made – (entry 4). Other silanes such as trimethoxysilane and diethox- toward this synthetically useful process26 61, which requires that ymethylsilane gave diminished yields (entries 5 and 6), and the cross-coupling partner (e.g., aryl halide or alkyl halide) could marginally lower yield was obtained when reducing the amount selectively capture an alkylnickel species generated through of PMHS to 2.5 equiv (entry 7). K3PO4·H2O was shown to be an iterative migratory insertion/β-hydride elimination. unsuitable base (entry 8). The addition of NaI as an additive To explore this nickel-catalyzed migratory hydrofunctionalization improves both the yield and rr, presumably by promoting the further, we recently investigated if a bromoalkyne, an unsaturated regeneration of NiH species (entry 9). An evaluation of solvents TIPS Ph 5 mol% NiI2 2O, 6 mol% L TIPS 5.0 equiv PMHS Ph + Br 2.0 equiv Na2CO3 10 mol% NaI DME (0.20 M) 1a 2a (1.5 equiv) 3a migratory alkene bromoalkyne hydroalkynylation entry deviation from standard conditions yield of 3a (%)* rr 1 none 91 (82) >99:1 2 NiBr2 instead of NiI2 xH2O 26 80:20 3 L1 instead of L 33 54:46 4 L2 instead of L 45 >99:1 5 (MeO)3SiH instead of PMHS 74 >99:1 6 (EtO)2MeSiH instead of PMHS 63 >99:1 7 2.5 equiv PMHS 83 >99:1 8 K3PO4 H2O instead of Na2CO3 42 76:24 9 w/o NaI 35 54:46 10 THF instead of DME 78 >99:1 11 56 85:15 Ph Ph N N N N N N L L1 L2 Fig. 2 Variation of reaction parameters. *Yields determined by GC using n-dodecane as the internal standard, the yield in parentheses is the isolated yield. †rr refers to regioisomeric ratio, representing the ratio of the major product to the sum of all other isomers as determined by GC analysis. PMHS polymethylhydrosiloxane, DME dimethoxyethane, TIPS triisopropylsilyl. NATURE COMMUNICATIONS | (2021) 12:3792 | https://doi.org/10.1038/s41467-021-24094-9 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-24094-9 revealed that THF was less effective than DME (entry 10), and coupling partners, regardless of the E/Z configuration or the posi- conducting the reaction at 40 °C gave inferior results (entry 11). tion of the C=C bond (Fig. 3b, 3o–3w). As expected, styrenes themselves smoothly undergo hydroalkynylation to produce the – ′ Substrate scope. With these optimal reaction conditions, we benzylic alkynylation product exclusively (Fig. 3c, 3x 3k ). Under these exceptionally mild reaction conditions, various substituents on examined the generality of the reaction. As shown in Fig. 3a, – ′ ′ ′ unactivated terminal alkenes bearing electron-donating (3c)or the aryl ring (3z 3e ) as well as heteroaromatic styrenes (3f , 3g ) electron-withdrawing (3d–3g) substituents on the remote aryl ring were also suitable for this reaction. are tolerated. A variety of
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