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]

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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.

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(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 protocol 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 functional groups are readily accom- In an effort to obtain enantioenriched benzylic alkynylation modated, including ethers (3c, 3h–3k, 3m), a trifluoromethyl products, the asymmetric version of NiH-catalyzed hydroalkynylation of styrenes was explored and the results are in Fig. 4.Itwas group (3d), and esters (3g, 3i). Importantly, tosylates (3j)and * fi triflate (3k) commonly used for further cross-coupling, all found that a chiral PyrOx ligand (S)-L under modi ed reaction remained intact. The reaction could also proceed with olefin conditions could produce the desired hydroalkynylation products in substrate having longer chain length between the starting C=C good yields and excellent ee. Styrenes with a variety of substituents bond and the remote aryl group, producing the benzylic alkyny- on the aromatic ring underwent asymmetric hydroalkynylation smoothly (5a–5q), including ethers (5d–5i), an easily reduced lation product exclusively although with a lower yield (3l). – Remarkably, both silyl and sterically hindered alkyl substituted aldehyde (5l), a nitrile (5m, 5n), and esters (5o 5q). Substituents ethynyl bromides work well in this reaction (3m, 3n). Moreover, a commonly used for further cross-coupling such as aryl chloride variety of unactivated internal alkenes also proved to be competent (5c), aryl bromide (5k), and boronic acid pinacol ester (5j)all

5 mol% NiI2 xH2O, 6 mol% L R' 5.0 equiv PMHS Ph Ph Ar R Ar + Br R' ()n 2.0 equiv Na2CO3 R 10 mol% NaI ()n N N 2 (1.5 equiv) 3 migratory 1 L alkene bromoalkyne hydroalkynylation a) from terminal aliphatic olefins R TIPS TIPS TIPS TIPS TIPS F Ph MeO2C

3c* R = OMe, 75% yield, >99:1 rr 3e p-F, 65% yield, >99:1 rr 3a 82% yield, >99:1 rr 3b 54% yield, >99:1 rr 3d* R = CF3, 92% yield, >99:1 rr 3f o-F, 75% yield, >99:1 rr 3g* 82% yield, >99:1 rr RO RO TIPS TIPS TIPS TBDPS Tr Ph PMP Ph MeO MeO

3h R = TBS, 57% yield, >99:1 rr 3j* R = Ts, 99% yield, >99:1 rr 3i* R = Ac, 78% yield, >99:1 rr 3k* R = Tf, 96% yield, >99:1 rr 3l >99:1 rr 3m* 95% yield, >99:1 rr 3n* 40% yield, >99:1 rr b) from unactivated internal olefins MeO MeO TIPS TIPS TIPS TIPS TIPS Ph CF3

from 1o (8:1 E/Z) from 1p (8:1 E/Z) from 1q (10:1 E/Z) from 1r (10:1 E/Z) from 1s (9:1 E/Z) 3o* 71% yield, >99:1 rr 3p 84% yield, >99:1 rr 3q >99:1 rr 3r >99:1 rr 3s* 69% yield, >99:1 rr

TIPS TIPS TIPS TIPS Ph Ph Ph Ph

OTBS nPent Ph Cy ()2 from 1t (8:1 E/Z) from 1u (3:1 E/Z) from 1v (5:1 E/Z) from 1w (1.3:1 E/Z) 3t >99:1 rr 3u 89% yield, >99:1 rr 3v 83% yield, >99:1 rr 3w* 45% yield, >99:1 rr c) from styrenes

TIPS from TIPS TIPS TIPS (E)-1z 3z p-OMe, 86% yield, >99:1 rr O Ph 1a' (1.3:1 E/Z) 3a' p-Cl, 94% yield, >99:1 rr 1b' (1.7:1 E/Z) 3b' p-Br, 96% yield, >99:1 rr R 1c' (1.5:1 E/Z) 3c' m-Bpin, 69% yield, >99:1 rr OTBS Et 1d' (1:1.8 E/Z) 3d' p-OCF3, 93% yield, >99:1 rr from 1x (1:2 E/Z) from 1y (1:9 E/Z) 1e' (1:2 E/Z) 3e' p-CO2Me, 76% yield, >99:1 rr from 1f' (>95:5 E/Z) 3x >99:1 rr 3y >99:1 rr 3f' 85% yield, >99:1 rr

TIPS TIPS TIPS TIPS S TIPS Ph Ph Ph

OTBS nBu Ph from 1g' (1:8 E/Z) from (E)-1h' from (E)-1i' from (Z)-1j' 3g' 91% yield, >99:1 rr 3h' 65% yield, >99:1 rr 3i' >99:1 rr 3j' 94% yield, >99:1 rr 3k' 57% yield, >99:1 rr

Fig. 3 NiH-catalyzed migratory hydroalkynylation of alkenes with bromoalkynes. Yield under each product refers to the isolated yield of puriﬁed product (0.20 mmol scale, average of two runs), rr refers to regioisomeric ratio, representing the ratio of the major product to the sum of all other isomers as † ‡ determined by GC analysis. *Diglyme was used as solvent. 10 mol% NiI2·xH2O, 12 mol% L, and 20 mol% NaI were used. DME (0.10 M) was used. TBS tert-butyldimethylsilyl, TBDPS tert-butyldiphenylsilyl; Tr trityl (triphenylmethyl).

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5 mol% NiI xH O, 6 mol% (S)-L* CF 2 2 Ar 3 2.5 equiv (MeO)3SiH R R' + Br R' O Ar N 2.5 equiv K3PO4 H2O 2.0 equiv NaI R PyrOx N 4 2 (1.5 equiv) 5 PhCF styrene bromoalkyne 3 hydroalkynylation (S)-L* tBu

TIPS TIPS OTBS TIPS TIPS TIPS from (E)-4e from 4f (1:6.1 E/Z)

Ph Cl MeO R from 4a (1:2 E/Z) from 4b (1:3 E/Z) from 4c (1:3 E/Z) from 4d (>95:5 E/Z) 5e R = Me, 82% yield, 94% ee 5a 71% yield, 94% ee 5b 66% yield, 94% ee 5c 51% yield, 96% ee 5d 91% yield, 90% ee 5f R = Et, 82% yield, 94% ee TIPS TIPS TIPS TIPS TIPS MeO MeO OMe R OHC from MeO 4j (1.5:1 E/Z) OTBS 4k (>95:5 E/Z)

MeO from 4g (1:3 E/Z) from 4h (5:1 E/Z) from 4i (1:2 E/Z) 5j R = Bpin, 82% yield, 90% ee from 4l (>95:5 E/Z) 5g 83% yield, 92% ee 5h 88% yield, 90% ee 5i 65% yield, 88% ee 5k* R = Br, 66% yield, 94% ee 5l 52% yield, 92% ee TIPS TIPS TIPS from 4m (>95:5 E/Z) from 4o (1:2 E/Z) TIPS TIPS tBuO C from 4n (1:1.6 E/Z) from 4p (>95:5 E/Z) 2 S Ph NC MeO2C OTBS iPr Ph

5m* p-CN, 62% yield, 94% ee 5o* p-CO2Me, 65% yield, 96% ee from 4q (>95:5 Z/E) from 4r (>95:5 E/Z) from (E)-4s 5n m-CN, 65% yield, 94% ee 5p m-CO2Me, 83% yield, 94% ee 5q 71% yield, 94% ee 5r 88% yield, 82% ee 5s 73% yield, 94% ee

TIPS TIPS TIPS TIPS TIPS from from R Ph 4u (1.9:1 E/Z) PMP F Ph Ph (E)-4y 4v (1.8:1 E/Z) 4z (1:2 E/Z) Ph OTBS X Et ()2 Br from 4t (1:9 E/Z) 5u R = Ph, 90% yield, 92% ee from 4w (3:1 E/Z) from (E)-4x 5y X = O, 81% yield, 88% ee 5t 81% yield, 92% ee 5v R = Tol, 84% yield, 94% ee 5w 89% yield, 94% ee 5x 70% yield, 90% ee 5z X = CH2, 62% yield, 94% ee

TIPS TIPS TIPS TES R Ph R from PMP O (E)-4b' PMP PMP (E)-4c' from (E)-4e' i O Pr CO2Me from (E)-4a' 5b' R = Ph, 66% yield, 84% ee from (E)-4e' 5f' R = TBS, 50% yield, 94% ee 5a' 67% yield, 88% ee 5c' R = PMP, 66% yield, 86% ee 5d' 87% yield, 92% ee 5e' 40% yield, 92% ee 5g' R = TBDPS, 42% yield, 96% ee

O O unsuccessful substrates

Tr TBSO Br nBu H H Ph PMP TIPS TIPS 2l' H H H H Br Ph with ligand (S)-L* with ligand (R)-L* from (E)-4h' from (E)-4i' 2m' 5h' 50% yield, 92% ee 5i' 66% yield, 86% ee 5j' 74% yield, 97:3 dr 5k' 81% yield, 5:95 dr

Fig. 4 NiH-catalyzed enantioselective hydroalkynylation of styrenes with bromoalkynes. Yield under each product refers to the isolated yield of puriﬁed product (0.20 mmol scale, average of two runs), single regioisomer was obtained unless otherwise noted. Enantioselectivities were determined by chiral

HPLC analysis. *NiBr2·diglyme used as catalyst, 1,2-dichloroethane used as solvent, 3.0 equiv NaI used. TES triethylsilyl. emerged unchanged. The substituents at β-position could also be substrate (Fig. 5a), chain-walking and subsequent asymmetric varied (5r–5c′). Alkyl bromides were compatible with the current alkynylation at benzylic position product ((S)-3i) was obtained reaction, providing a synthetic handle for further derivatization (5y, with excellent ee (90% ee) as major isomer (90:10 rr). When the 5z). β-Unsubstituted styrenes were also compatible (5d′, 5j′, 5k′). reaction was conducted on a 5 mmol scale, the functionalized The scope of bromoalkynes was also explored and a range of chiral benzylic alkyne (5e) was obtained in high yield and with different sterically hindered substituents at the β-position, including excellent enantioselectivity (Fig. 5b). To highlight the synthetic silyl and alkyl-substituted ethynyl bromides were shown to be viable utility of the method, subsequent derivatizations were carried out substrates (5e′–5i′). However, it should also be noted that the (Fig. 5c). Desilylation of 5e yielded the enantioenriched terminal less steric hindered alkyl-substituted ethynyl bromide (2l′)andaryl- alkyne (6), which could further undergo a click reaction to form 7 substituted ethynyl bromide (2m′) were unsuccessful substrates70 or a hydration reaction to form 8. The semi-hydrogenation of and could easily undergo decomposition under the current alkyne (5a) by DIBAL-H (diisobutylaluminum hydride) could be conditions. highly stereoselective, giving the Z-alkene (9). In addition, oxidative cleavage of the triple bond in 5e could afford the corresponding chiral carboxylic acid (10). Discussion To gain further insight into the mechanism of the hydro- The asymmetric migratory hydroalkynylation could also be rea- metallation process, isotope labeling experiments were conducted. lized. In a preliminary experiment with 3-aryl-1-propene (1i)as As shown in Fig. 5d, the use of the deuterated trans-alkene (E-4h-D)

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a Preliminary result of enantioselective migratory hydroalkynylation e Crossover experiment: no intermolecular H/D scrambled crossover products AcO AcO TIPS TIPS D D TIPS + D D Br standard conditions MeO D D MeO as in Fig. 4 Et 2a (1.5 equiv) 1i (S)-3i 78% yield, 90% ee, 90:10 rr D D D D D b Gram-scale experiment standard conditions D PMP D as in Fig. 3 D D H D + Br TIPS TIPS PMP 1k'-D (1.0 equiv) 3k'-D 81% yield standard conditions Et 3.0 equiv 2a as in Fig. 4 5e 75% yield, 94% ee + 4e 2a + TIPS (5 mmol) (1.5 equiv) (1.24 g) PMP c Transformation of the enantioenriched benzylic alkynes PMP TIPS N N Et CuTc DIBAL-H PMP N SO Ar 1z (1.0 equiv) 3z (no D-incorporation) 2 40% yield ArSO2N3 Ar = TIPS Et p-AcNHC H (from 5a) Et 6 4 PMP 9 98% yield, 94% ee PMP TBAF 7 75% yield, 96% ee D D TIPS 5e THF Et 6 D D 3 78% yield, 94% ee D D RuCl PMP CO2H 4 PMP NaIO CHO D D D D D D Et CpRu(MeCN)3PF6 Et 8 standard conditions 10 60% yield, 96% ee L, H2O/NMP, rt 48% yield, 94% ee D as in Fig. 4 D D H D 1k'-D (1.0 equiv) 5n'-D 89% yield d Isotopic labeling: NiH syn-hydrometallation is not the enantio-determining step 3.0 equiv 2a OMe + + TIPS OMe standard conditions TIPS as in Fig. 4 PMP OTBS PMP 1.5 equiv 2a D (0.55 D) H OTBS Et (0.45 D) H 4e (1.0 equiv) 5e (no D-incorporation) 74% yield, 94% ee (E)-4h-D 5h-D 81% yield, 0.55:0.45 dr, 92% ee

Fig. 5 Enantioselective migratory hydroalkynylation, gram-scale, derivatization, and isotopic labeling experiments. a Preliminary result of enantioselective migratory hydroalkynylation. b Gram-scale experiment. c Transformation of the enantioenriched benzylic alkynes. d Isotopic labeling experiment. e Crossover experiment. led to the formation of both diastereomers in approximately equal flash column chromatography (petroleum ether/EtOAc) for each substrate. See amounts (0.55:0.45 dr), which indicated that the syn-hydrometalla- Supplementary Information for more detailed experimental procedures and tion is not the enantio-determining step because if it was, a dia- characterization data for all products. stereomerically pure 5h-D should be formed. This observation is Enantioselective NiH-catalyzed hydroalkynylation of styenes. In a nitrogen- consistent with our initial mechanistic proposal that the benzylic filled glove box, to an oven-dried 8 mL screw-cap vial equipped with a magnetic stir * stereocentre is formed through rapid homolysis of the alkyl-Ni(III) bar were added NiI2·xH2O (3.8 mg, 5.0 mol%), (S)-L (3.3 mg, 6.0 mol%), bond and subsequently enantioconvergent process, reforming only K3PO4·H2O (115.1 mg, 2.5 equiv), NaI (60.0 mg, 2.0 equiv) and anhydrous PhCF3 one Ni(III) enantiomer from Ni(II) and benzylic radical (see Fig. 1c, (1.0 mL). The mixture was stirred for 20 min at room temperature (stirred at μ ii). Furthermore, no intermolecular H/D scrambled crossover pro- 800 rpm) before the addition of (MeO)3SiH (64 L, 0.50 mmol, 2.5 equiv). Stirring was continued for an additional 5 min before the addition of olefin 4 (0.20 mmol, ducts were obtained in both migratory and asymmetric hydroalk- 1.0 equiv) and bromoalkyne 2 (0.30 mmol, 1.5 equiv). The tube was sealed with a ynylation conditions, revealing that hydrometallation of NiH/NiD teflon-lined screw cap, removed from the glove box and the reaction was stirred at species to styrene is irreversible (Fig. 5e). 0 °C for up to 12 h (the mixture was stirred at 800 rpm). After the reaction was In conclusion, we report a NiH-catalyzed strategy to form complete, the reaction was quenched upon the addition of H2O, and the mixture was extracted with EtOAc. The organic layer was concentrated to give the crude functionalized benzylic alkynylation products, which are versatile product. n-Dodecane (20 μL) was added as an internal standard for GC analysis. synthetic intermediates. Both migratory hydroalkynylation and The product was purified by flash column chromatography (petroleum ether/ asymmetric hydroalkynylation can be realized. These two mild, EtOAc) for each substrate. The enantiomeric excesses (% ee) were determined efficient, and straightforward processes tolerate a wide range of by HPLC analysis using chiral stationary phases. See Supplementary Information for more detailed experimental procedures and characterization data for all functional groups on both the alkene and bromoalkyne compo- products. nents. A broad substrate scope as well as synthetic utility of this protocol have been demonstrated. An investigation of the Data availability mechanism and the development of a migratory enantioselective The authors declare that the main data supporting the findings of this study, including version of this transformation are currently in progress. experimental procedures and compound characterization, are available within the article and its supplementary information files, or from the corresponding author upon reasonable request. Methods NiH-catalyzed migratory hydroalkynylation of alkenes. In a nitrogen-filled glove box, to an oven-dried 8 mL screw-cap vial equipped with a magnetic stir bar Received: 12 March 2021; Accepted: 24 May 2021; were added NiI2·xH2O (3.8 mg, 5.0 mol%), L (4.3 mg, 6.0 mol%), Na2CO3 (42.4 mg, 2.0 equiv), NaI (3.0 mg, 10.0 mol%) and anhydrous DME (1.0 mL). The mixture was stirred for 20 min at room temperature (stirred at 800 rpm) before the addition of PMHS (60 μL, 1.0 mmol, 5.0 equiv). Stirring was continued for an additional 5 min before the addition of olefin 1 (0.20 mmol, 1.0 equiv) and bromoalkyne 2 (0.30 mmol, 1.5 equiv). The tube was sealed with a teflon-lined screw cap, removed References from the glove box and the reaction was stirred at 25 °C for up to 16 h (the mixture 1. Trost, B. M. & Li, C.-J. Modern Alkyne Chemistry: Catalytic and Atom- was stirred at 1000 rpm). After the reaction was complete, the reaction was Economic Transformations (Wiley-VCH, Weinheim, 2015). quenched upon the addition of H2O, and the mixture was extracted with EtOAc. 2. Dong, X.-Y. et al. A general asymmetric copper-catalysed Sonogashira C μ The organic layer was concentrated to give the crude product. n-Dodecane (20 L) (sp3)–C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019). was added as an internal standard for GC analysis. The product was purified by

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58. Wang, J.-W. et al. Catalytic asymmetric reductive hydroalkylation of enamides talents introduction of Jiangsu Province (group program), and Fundamental Research and enecarbamates to chiral aliphatic amines. Nat. Commun. 12, 1313 Funds for the Central Universities (020514380263). (2021). 59. Wang, X.-X. et al. NiH-Catalyzed reductive hydrocarbonation of enol esters Author contributions and ethers. CCS Chem. 3, 727–737 (2021). 60. Wang, S. et al. Enantioselective access to chiral aliphatic amines and alcohols X.J., Y.W., and S.Z. designed the project. X.J., B.H., Y.X., M.D., Z.G., Y.W., and S.Z. co- via Ni-catalyzed hydroalkylations. Nat. Commun. 12, 2771 (2021). wrote the manuscript, analyzed the data, discussed the results, and commented on the 61. Zhou, F. & Zhu, S. Enantioselective hydroalkylation of α,β-unsaturated amides manuscript. X.J., B.H., Y.X., M.D., and Z.G. performed the experiments. All authors through reversed syn-hydrometallation of NiH. ChemRxiv https://doi.org/ contributed to discussions. 10.26434/chemrxiv.13681579.v1 (2021). 62. Lv, X.-Y., Fan, C., Xiao, L.-J., Xie, J.-H. & Zhou, Q.-L. Ligand-enabled Ni- Competing interests catalyzed enantioselective hydroarylation of styrenes and 1,3-dienes with The authors declare the following competing interest(s): a patent for the synthesis of arylboronic acids. CCS Chem. 1, 328–334 (2019). AMG 837 using this method has been ﬁled. 63. Chen, Y.-G. et al. Nickel-catalyzed enantioselective hydroarylation and hydroalkenylation of styrenes. J. Am. Chem. Soc. 141, 3395–3399 (2019). Additional information 64. Zhang, W.-B., Yang, X.-T., Ma, J.-B., Su, Z.-M. & Shi, S.-L. Regio- and Supplementary information The online version contains supplementary material enantioselective C–H cyclization of pyridines with alkenes enabled by a available at https://doi.org/10.1038/s41467-021-24094-9. nickel/N-heterocyclic carbene catalysis. J. Am. Chem. Soc. 141, 5628–5634 (2019). Correspondence and requests for materials should be addressed to Y.W. or S.Z. 65. He, Y., Liu, C., Yu, L. & Zhu, S. Ligand-enabled nickel-catalyzed redox-relay Peer review information Nature Communications thanks the anonymous reviewer(s) for migratory hydroarylation of alkenes with arylborons. Angew. Chem. Int. Ed. their contribution to the peer review of this work. Peer reviewer reports are available. 59, 9186–9191 (2020). 66. Yu, R., Rajasekar, S. & Fang, X. Enantioselective nickel-catalyzed migratory Reprints and permission information is available at http://www.nature.com/reprints hydrocyanation of nonconjugated dienes. Angew. Chem. Int. Ed. 59, – 21436 21441 (2020). ’ 67. Schley, N. D. & Fu, G. C. Nickel-catalyzed Negishi arylations of propargylic Publisher s note Springer Nature remains neutral with regard to jurisdictional claims in ﬁ bromides: a mechanistic investigation. J. Am. Chem. Soc. 136, 16588–16593 published maps and institutional af liations. (2014). 68. Zhu, F.-L. et al. Enantioselective copper-catalyzed decarboxylative propargylic alkylation of propargyl β-ketoesters with a chiral ketimine P,N,N-ligand. Open Access This article is licensed under a Creative Commons Angew. Chem. Int. Ed. 53, 1410–1414 (2014). Attribution 4.0 International License, which permits use, sharing, 69. Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. adaptation, distribution and reproduction in any medium or format, as long as you give Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering appropriate credit to the original author(s) and the source, provide a link to the Creative a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. Commons license, and indicate if changes were made. The images or other third party J. Am. Chem. Soc. 137, 4896–4899 (2015). material in this article are included in the article’s Creative Commons license, unless 70. Ziadi, A., Correa, A. & Martin, R. Formal γ-alkynylation of ketones via Pd- indicated otherwise in a credit line to the material. If material is not included in the – – catalyzed C C cleavage. Chem. Commun. 49, 4286 4288 (2013). article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ Acknowledgements licenses/by/4.0/. Research reported in this publication was supported by NSFC (21822105, 21772087), NSF of Jiangsu Province (BK20190281, BK20201245), Six Kinds of Talents Project of Jiangsu Province (JNHB-003), programs for high-level entrepreneurial and innovative © The Author(s) 2021

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