Alkenes

Redox-Neutral Nickel(II) Catalysis: Hydroarylation of UnactivatedAlkenes with Arylboronic AcidsDao-Ming Wang, Wang Feng, Yichen Wu, Tao Liu, and Peng Wang*

Abstract: Reported here is the discovery of a redox-neutralNiII/NiII catalytic cycle which is capable of the linear-selectivehydroarylation of unactivated alkenes with arylboronic acidsfor the first time. This novel catalytic cycle, enabled by the useof an electron-rich diimine ligand, features broad substratescope, and excellent functional-group and heterocycle compat-ibility under mild reaction conditions in the absence ofadditional oxidants and reductants. Mechanistic investigationsusing kinetic analysis and deuterium-labelling experimentsrevealed the protonation to be the rate-determining step in thisredox-neutral catalysis, and the reversible chain-walkingnature of the newly developed diimine-Ni catalyst.

The state-of-the-art of nickel catalysis is laid on the avail-ability of various oxidation states (Ni0–NiIV), outstandingability to coordinate to unsaturated molecules, facile oxida-tive addition and reductive elimination, homolytic Ni�C bondcleavage, and exceptional reactivity of organonickel species.[1]

Those characteristics of nickel open a plethora of catalyticopportunities, and have led to the discovery of exceptionalcatalytic systems and numerous fascinating synthetic appli-cations via two-electrons or single-electron redox catalyticprocesses.[2–10] However, a redox-neutral process for reactiondevelopment in which the valence of nickel remainsunchanged is less explored,[11] and remains a significantchallenge due to the capricious nature of nickel. Suchredox-neutral process will allow the carbon–carbon orcarbon–heteroatom bond formation with high efficiency andremarkable functional group tolerance under mild conditions,and will avoid the use of additional stoichiometric oxidants orreductants normally required in redox processes. One well-known NiII-involved redox neutral process is salicylaldimi-nato-NiII or diimine-NiII catalyzed olefin polymerization,pioneered by Brookhart[12a] and Grubbs[12b] at 1990s. In thisprocess, an alkyl-NiII species is capable of migratory insertionto a coordinated alkene, followed by the propagation. Never-

theless, applications of the similar catalytic process in alkenefunctionalization are barely reported.

Transition metal catalyzed hydroarylation of abundantalkenes with commercially available aryl sources representsas an effective and attractive manner to construct carbon-carbon bond.[13] As such, tremendous efforts have been madein the last decades towards the development of efficient andregioselective hydroarylation reactions of alkenes usingvarious types of aryl sources. However, direct regioselectivehydroarylation of unactivated aliphatic alkenes[14] is relativelyrare in comparison to that of styrenes and dienes, and stillsuffers from some limitations including formation of Heck-type byproduct via rapid b-hydride elimination, isomerizationof starting material, difficulty controlling of the regioselec-tivity, especially without directing-group assistance.[15]

Recently, much attention has been paid to nickel-catalyzedhydroarylation reactions of alkenes due to the uniquecharacteristics, abundance, low cost of nickel catalyst usingaryl halides, arenes, and aryl borons as aryl sources.[16–18]

Starting from aryl halides, Liu[16a] and Lalic[16e] have achievedthe Ni-catalyzed linear-selective hydroarylation of styrenesand unactivated alkenes using silane as reductant. In 2017,Zhu[16c] and co-workers have reported the remote-branchselective arylation via Ni-H initiated chain-walking process.(Scheme 1a). Shenvi reported an alternative dual metalcatalysis strategy for branch-selective hydroarylation ofalkenes via metal–hydrogen atom transfer.[16b,d] Very recently,Nakao and Hartwig have demonstrated an elegant Ni0/NHC-catalyzed linear selective hydroarylation of unactivatedolefins with arenes via ligand–ligand hydrogen transfer(LLHT) mechanism,[17a] albeit excess of simple arenes arerequired (Scheme 1b). Despite of the significant progresses,those redox catalytic processes typically suffer from the use ofstoichiometric reductants or oxidants alongside harsh reac-tion conditions, complex catalytic system, or limited scope.One breakthrough by Zhou demonstrates a Ni0 enabledbranch-selective hydroarylation of styrenes with arylboronicacids under redox-neutral conditions, where the Ni-H couldbe readily generated upon the oxidative addition ofMeOH.[18a] Later, Zhao and Zhou have expanded this conceptto directing-group-assisted unactivated alkenes with linearselectivity (Scheme 1c, below).[18b] However, this incredibleprotocol with arylboronic acids which relied on the Ni-Hspecies could not be compatible with simple aliphatic alkenes.Inspired by the NiII-catalyzed olefin polymerization pro-cess,[12] we hypothesized that a redox neutral process might besuitable for the hydroarylation of unactivated aliphaticalkenes (Scheme 1d). During the whole process, the valenceof the nickel catalyst remains unchanged which is unusual fornickel catalysis. Herein, we present our preliminary results

[*] D.-M. Wang, W. Feng, Dr. Y. Wu, T. Liu, Prof. Dr. P. WangState key laboratory of organometallic chemistry, Center for excel-lence in molecular synthesis, Shanghai Institute of OrganicChemistry, CAS345 Lingling Road, Shanghai 200032 (P. R. China)E-mail: pengwang@sioc.ac.cn

Prof. Dr. P. WangCAS Key Laboratory of Energy Regulation Materials, ShanghaiInstitute of Organic Chemistry, CAS345 Lingling Road, Shanghai 200032 (P. R. China)

Supporting information and the ORCID identification number(s) forthe author(s) of this article can be found under:https://doi.org/10.1002/anie.202009195.

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Zitierweise: Angew. Chem. Int. Ed. 2020, 59, 20399–20404Internationale Ausgabe: doi.org/10.1002/anie.202009195Deutsche Ausgabe: doi.org/10.1002/ange.202009195

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http://orcid.org/0000-0002-0639-0412http://orcid.org/0000-0002-0639-0412http://orcid.org/0000-0002-6442-3008https://doi.org/10.1002/anie.202009195http://dx.doi.org/10.1002/anie.202009195http://dx.doi.org/10.1002/ange.202009195http://crossmark.crossref.org/dialog/?doi=10.1002%2Fange.202009195&domain=pdf&date_stamp=2020-09-04

using redox-neutral NiII catalysis as a complementaryapproach for linear-selective hydroarylation of unactivatedaliphatic alkenes.

With the concept in mind, we investigated the hydro-arylation of unactivated alkenes with arylboronic acid, whichis not compatible with previous Ni0-catalyzed process. Aftersystematically evaluation of the reaction parameters, we arepleased to find the linear-selective hydroarylation of unac-tivated alkenes 1 with phenylboronic acid proceeded in 29%yield with a linear/branch selectivity of 90/10, along withisomerization and oxidative Heck-type byproducts, in thepresence of Ni(acac)2 and CsHCO3 in tert-amyl alcohol. Asshown in Table 1, the ligand effects were investigated next forthis reaction. Bipyridine ligand (L1), 1,10-phenanthrolineligand (L2), and diamine ligand (L3) led to inferior results.Mono phosphine ligand, superior ligand in Ni0-catalyzedhydroarylation of styrenes[18a] and directing group tetheredalkenes,[18b] was unreactive under our conditions, providingthe olefin isomerization byproduct in high yields. Thisexperimental result demonstrated the fundamental differenceof the redox-neutral NiII catalysis in comparison to the Ni-Hinitiated reactions. Pyridine-imine ligand (L5), and pyridine-oxazoline ligands (L6–7) could not significantly accelerate theprocess, while bis-oxazoline ligand (L8) promoted thisreaction to 55 % yield along with 15% yield of the isomer-ization byproduct. To our delight, diimine ligands (L9–18)have the capability of suppression of the Heck-type byprod-uct 5, probably due to sluggish b-H elimination. Accordingly,

we turned our attention to modify the diimine ligands, andfound diacetyl-derived ligand L10 could shut down theisomerization reaction in comparison to other scaffolds.Substitution on the para-position of aromatic ring of diimineligands will allow for significant modulation of electronicproperties, and normally the electron-rich substitutionsprovided higher yields in comparison with the electron-deficient ligands (L14–17). Noteworthy, para-OH substitutedligand L18 could further enhance the yield to 83% with a 91/9linear to branch selectivity. We hypothesized that the phenolichydroxy group could convert to phenoxide ion in the presenceof base, hence provides a highly electron-rich diimine ligandwhich is capable of stabilizing the NiII-catalyst in the wholecatalytic cycle. The development of this novel phenolichydroxy group containing diimine ligand is noteworthy, andit plays a significant role in accelerating our hydroarylationreaction via redox-neutral NiII catalysis.

With the optimized reaction conditions in hand, we set outto evaluate scope of arylboronic acids first, providingcorresponding d-arylated N-phenylpentanamides in highregioselectivity and high yields (Table 2). In general, theelectron-deficient arylboronic acids provided a slightly higherlinear/branch selectivity. Good functional group compatibilitywas observed with tolerance of methoxy (3c), trifluorome-thoxy (3d), trimethylsilyl (3e), methylthio (3 f), fluoro (3g),chloro (3h), bromo (3 i), ester (3j), acetyl (3k), nitrile (3 l),trifluoromethyl (3 m), difluoromethyl (3n), and dimethyl-amine (3q). Ortho-, meta-, para-, and multisubstituted

Scheme 1. Ni-catalyzed hydroarylation of alkenes.

Table 1: Ligand evaluation for NiII-catalyzed linear-selective hydroaryla-tion of unactivated alkenes.[a,b]

[a] Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol, 1.5 equiv ),Ni(acac)2 (10 mol%), Ligand (10 mol%), CsHCO3 (29.1 mg, 1.5 equiv),t-Amyl-OH (1.0 mL), 80 8C, N2, 10 h. [b] The yield was determined by1H NMR using dibromomethane as the internal standard. The selectivityof the linear- and branch-selective products was determined by GCanalysis.

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arylboronic acids were all suitable coupling partners for thislinear selective hydroarylation reaction. Moreover, hetero-cyclic arylboronic acids, including benzofuran, quinoline, anddibenzothiophene derivatives, also worked well (3 w–y),showcasing the utility of this reaction for medicinal chemistrywhere heterocyclic motifs are prevalent.

Next, we turned our focus to evaluating unactivatedalkenes with 4-methoxycarbonylphenylboronic acid (2j).Experimental results show that this reaction exhibited anexceptionally broad scope of alkenes (Table 3). A variety offunctional groups are well tolerated under the redox-neutralconditions, including amide, ester, ether, alcohol, Br, Cl, CF3,and amine, providing the desired products in good yields withexcellent linear selectivity. Substituents at the b-position tothe alkene are compatible (7d,e), while substituent at allylicposition provided lower yield (7 f). 1,1-Disusbtituted alkenes(7t) proceeded in moderated yield probably due to the sterichindrance. Given the prevalence of heterocycles in pharma-ceuticals and bioactive molecules, the heterocycle-containingsubstrates were evaluated. Our approach displayed a highlevel of tolerance towards aromatic and non-aromatic hetero-

cycles (7u–ad), including indoline, morpholine, piperidine,piperazine, carbazole, indole, phenothiazine, quinoline, furanand thiophene. The mild reaction conditions and high func-tional group tolerance could facilitate the late-stage function-alization of biorelevant compounds in high yields, such assubstrates from cholesterol (7ae), estrone (7 af), indometha-cin (7ag), and isoxepac (7ah).

To gain mechanistic insights of this reaction, three majorreaction pathways are considered based on the previousreports and our hypothesis (Scheme 2). Pathway A involvesa formation of Ni0 by double transmetalation of arylboronicacid and sequentially reductive elimination, where a biarylwill generate via homocoupling of arylboronic acid. Oxidativeaddition with tert-amyl alcohol to deliver the key [LNiII�H]species, followed by the migratory addition to unactivatedalkene, transmetalation of arylboronic acid, reductive elim-ination to furnish the targeted product. In pathway B, thereaction happened via transmetalation of arylboronic acid,and sequentially interrupted Heck reaction to form the keyalkyl-NiII intermediate (Int NiII). This key intermediate couldundergo the protonation to provide the product and regen-erate the NiII catalyst. The difference of pathway C frompathway B is the formation of the Heck product, which couldbe further reduced in the presence of Ni-H species to providethe final product. Identification of these three scenarios couldfacilitate the development of new reactions based on similarmechanism.

Control experiments were conducted to understand thereaction process. Heck product 8 are unreactive understandard reaction conditions ruled out the proposed pathwayC where the Heck product 8 could convert to the hydro-arylated product via in situ reduction (Scheme 3 a). Havingquickly ruled out pathway C, we set our attention todifferentiating between the NiII-H initated pathway A andthe Ar-NiII initiated pathway B. Replacement of the Ni(acac)2with Ni(COD)2 led to 28 % yield of isomerization productsrather than the hydroarylated product. The formation ofisomerization products might indicate the formation of Ni-Hspecies via oxidative addition of alcohol with Ni0 under ourconditions, which is consistent with Zhou�s observation.Further testing using Ni(COD)2/PPh3 as the catalytic systemled to similar results. However, the desired hydroarylationdidn�t occur despite of the formation of Ni-H species in thereaction system (Scheme 3b). We also carefully checked ourreaction system, where no dimerization of arylboronic acid

Table 2: The scope with respect to the arylboronic acid.[a,b]

[a] Reaction conditions: 1 (35.0 mg, 0.2 mmol), 2 (0.4 mmol, 2.0 equiv),Ni(acac)2 (5.1 mg, 10 mol%), L18 (8.7 mg, 10 mol%), CsHCO3(77.6 mg, 2.0 equiv), t-Amyl-OH (1.0 mL), 80 8C, 24 hours. [b] Yield ofisolated product; the selectivity of the linear- and branch-selectiveproducts was determined by GC analysis or by 1H NMR of the crudereaction mixture. [c] 90 8C, 12 h.

Scheme 2. Plausible mechanistic pathways.

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and isomerization byproduct were detected. Those evidencesindicated the Ni0 formation process (pathway A) is unlikelyinvolved in our reaction system. To further confirm theassumption, we have synthesized the diimine-Ni0 complex[L17-Ni0] following Chirik�s procedure (Scheme 3c).[19]

Employing stoichiometric diimine-Ni0 complex as catalyst,60% yield of isomerizing inner alkenes was observed in crude1H NMR. However, we still could not detect the desiredhydroarylated products, which is inconsistent with previousobservation. However, the reaction with aryl bromide asarylating reagent gave the desired product in 20 % yield. Thisoutput might be elucidated by the formation of the keyintermediate [L17-NiII-Ar] via oxidative addition of arylbromide with [L17-Ni0] complex, which could also begenerated by transmetalation with arylboronic acid in ourreaction system. In addition, our protocol is also compatiblewith styrene-type substrate, giving the hydroarylated product10 in 60 % yield with remarkable linear selectivity. Switching

to Ni(COD)2/PtBu3 catalytic sys-

tem,[18a] the reaction underwent the[Ni�H] initiated reaction pathway,led to branch-selective product in99% yield. The switch of the regio-selectivity with 4-tert-butylstyrenealso revealed a different reactionpathway for our reaction. Overall,pathway B, containing a Ar-NiII

initiated insertion to alkenes anda sequential protonation, seems tobe more reasonable.

To gain insight into the details ofpathway B, we performed reactionprogress kinetic analysis (RPKA)[20]

monitored by analyzing reactionmixture of reaction between 3-bute-nylbenzene (6q) and 4-methoxycar-bonylphenylboronic acid (2j ; seethe Supporting Information). “Dif-ferent excess” experiments revealthat this reaction is zero order toalkene and arylboronic acid (seeFigure S5 in the Supporting Infor-mation). Next, experiments withdifferent concentration of [Ni-(acac)2/L18] complex were per-formed to evaluate the order of[Ni] catalyst (Figure S9). When nor-malizing the rates as a function of[Ni] catalyst, good overlay of thecurves indicates a mechanism that isthe first order with regard to [Ni-(acac)2/L18] catalyst. After weruled out the pathway A and path-way C, the first order with regard to[Ni(acac)2/L18] catalyst in thekinetic experiments indicated theprotonation of the Int NiII inter-mediate in pathway B was the rate-limiting step.

To validate the hydrogen source in the products, we nextperformed various experiments using deuterium-labelledarylboronic acid and deuterium-labelled tert-amyl alcohol,respectively. No H/D exchange happened treating substrate1 and product 3j in deuterium-labelled tert-amyl alcohol inthe absence of arylboronic acid under the standard conditions(Scheme 4a). The reaction of ArB(OD)2 with alkene 1 in t-AmylOH gave undeuterated product ruled out ArB(OD)2 ashydrogen source in this process (Scheme 4 b). Treatment of allreactants in t-AmylOD led to partially deuterated product atthermodynamically stable a-position to carbonyl group(0.15 D) and benzylic position (0.52 D). Interestingly, low-ering the loading of CsHCO3 in t-AmylOD gave higherdeuterium contribution (totally 0.95 D vs. 0.67 D) in theproduct. Given complex kinetic orders for CsHCO3 wasobserved during reaction progress kinetic analysis (seesupporting information), we hypothesized that the hydrogenin the product mainly come from t-AmylOH, and partially

Table 3: The scope with respect to the alkenes.[a,b]

[a] Reaction conditions: 6 (0.2 mmol), 2 j (0.4 mmol, 2.0 equiv), Ni(acac)2 (5.1 mg, 10 mol%), L18(8.7 mg, 10 mol%), CsHCO3 (77.6 mg, 2.0 equiv), t-Amyl-OH (1.0 mL), 80 8C, 24 hours. [b] Yield ofisolated product; the selectivity of the linear- and branch-selective products was determined by GCanalysis or by 1H NMR of the crude reaction mixture. [c] 90 8C, 12 h.

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from bicarbonate. Notably, the deuterium is not observed inother positions rather than thermodynamically stable a-position to carbonyl group (0.15 D) and benzylic positiondisclosed that our diimine-NiII catalyst is capable of rapidchain-walking process (b-H elimination and reinsertion), andfurther confirmed the protonation is the rate-determiningstep in the catalytic cycle.

Based on the aforementioned detailed mechanistic stud-ies, a plausible mechanism was depicted in Figure 1. Thereaction could finish via a redox-neutral catalytic cycle,including transmetalation of arylboronic acid to L-NiII,migratory insertion to unactivated alkenes, and finally theprotonation to regenerated the NiII species. In addition, thekinetic experiments unveiled that the protonation step is therate determining step in the redox-neutral catalytic cycle,following rapid transmetalation and migratory insertion.More importantly, the kinetic studies along with the deute-rium-labelling experiments indicated the rapid nickel-walkingnature of our newly developed catalyst. The nickel walking

nature, along with the protonation as rate-determining stepwould open a new avenue for development of remotedifunctionalization of unactivated alkenes via redox-neutralNiII catalysis.

In summary, a redox-neutral NiII catalysis for linear-selective hydroarylation of a wide range of unactivatedaliphatic alkenes has been disclosed. The key to realizingthis reaction is the development of an electron-rich diimineligand which is capable of stabilizing the capricious nickel,and accelerating the linear-selective hydroarylation.

Acknowledgements

We gratefully acknowledge the Shanghai Institute of OrganicChemistry, State Key Laboratory of Organometallic Chemis-try, Shanghai Rising-Star Program (20QA1411400), and the

Scheme 3. Control experiments.

Scheme 4. Deuterium-labeling experiments.

Figure 1. Proposed redox neutral NiII/NiII catalytic cycles.

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National Natural Science Foundation of China (21821002) forfinancial support.

Conflict of interest

The authors declare no conflict of interest.

Keywords: alkenes · hydroarylation · nickel ·reaction mechanisms · synthetic methods

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Manuscript received: July 3, 2020Revised manuscript received: August 2, 2020Accepted manuscript online: August 3, 2020Version of record online: September 4, 2020

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