molecules

Article Cross-Coupling Reaction of Allylic Ethers with Aryl Grignard Reagents Catalyzed by a Nickel Pincer Complex

Toru Hashimoto * , Kei Funatsu, Atsufumi Ohtani, Erika Asano and Yoshitaka Yamaguchi *

Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan; [email protected] (K.F.); [email protected] (A.O.); [email protected] (E.A.) * Correspondence: [email protected] (T.H.); [email protected] (Y.Y.); Tel.: +81-45-339-3940 (T.H.); +81-45-339-3932 (Y.Y.)


Academic Editor: Kouki Matsubara
 Received: 30 May 2019; Accepted: 18 June 2019; Published: 21 June 2019

Abstract: A cross-coupling reaction of allylic aryl ethers with arylmagnesium reagents was investigated using β-aminoketonato- and β-diketiminato-based pincer-type nickel(II) complexes as catalysts. An β-aminoketonato nickel(II) complex bearing a diphenylphosphino group as a third donor effectively catalyzed the reaction to afford the target cross-coupled products, allylbenzene derivatives, in high yield. The regioselective reaction of a variety of substituted cinnamyl ethers proceeded to give the corresponding linear products. In contrast, α- and γ-alkyl substituted allylic ethers afforded a mixture of the linear and branched products. These results indicated that the coupling reaction proceeded via a π-allyl nickel intermediate.

Keywords: pincer-type nickel(II) complex; cross-coupling; allylic ether

1. Introduction Transition metal-catalyzed cross-coupling reactions are efficient and widely utilized synthetic protocols for constructing carbon–carbon bonds [1]. The reactions of allylic electrophiles with aryl metal reagents provide promising methodologies for the formation of C(sp3)–C(sp2) bonds. Allylic electrophiles with efficient leaving groups, such as allylic halides, acetates, and phosphates, are commonly used in these reactions [2–6]. In contrast to these allylic electrophiles, allylic ethers have been considered less-reactive electrophiles in cross-coupling reactions, whereas these electrophiles are easily accessible, cheap, and easy to handle. Therefore, the development of effective metal catalysts for coupling reactions utilizing allylic ethers as electrophiles in a highly regioselective manner has attracted considerable attention. The choice of the metal catalyst is critical for linear and branched selectivity. Although precious metals such as Pd and Ir have been extensively explored in selective allylic substitution reactions [2–4], recent efforts have focused on first-row late transition-metals such as Cu, Co, Fe, and Ni, whose complexes act as highly active catalysts. For example, Feringa reported the asymmetric allylic alkylation of acyclic allylic ethers with organolithium reagents using a Cu/phosphoramidite system [7]. Oshima and Yorimitsu reported a cobalt-catalyzed cross-coupling reaction of allylic ethers with Grignard reagents in a linear manner [8]. Iron catalysts also enable the allylic arylation reaction to be performed [9–12]. Recently, Ni pincer complexes have been reported as effective catalysts for the coupling reaction of allylic ethers with aryl zinc reagents [13]. In recent years, tridentate pincer-type complexes have generated significant interest because the pincer-type ligand stabilizes the metal complex and its properties can be tuned to achieve optimal reactivity [14–25]. We have recently reported the synthesis of a range of pincer-type nickel(II) complexes

Molecules 2019, 24, 2296; doi:10.3390/molecules24122296 www.mdpi.com/journal/molecules Molecules 2019, 24, 2296 2 of 12 Molecules 2019, 24 FOR PEER REVIEW 2

(nickel(II)1a–d) utilizing complexes a combination (1a–d) ofutilizingβ-aminoketonato a combination or β-diketiminato of β-aminoketonato frameworks or with β- adiketiminato third donor suchframeworks as an amino with a or third phosphino donor such group as [an26 ,amino27]. Our or systematicphosphino studygroup on[26,27 these]. Our nickel(II) systematic complexes study revealedon these thatnickel(II) modifying complex the ligandes reveal frameworked that has modif a significantying the influence ligand framework on the catalytic has a performance significant ininfluence the cross-coupling on the catalytic reaction performance of aryl halides in withthe arylmagnesium cross-coupling reagents. reaction In of particular, aryl halides nickel(II) with complexesarylmagnesium1b and reagents.1d bearing In a diphenylphosphinoparticular, nickel(II) group compl as theexes third donor1b and enable 1d the bearing utilization a ofdiphenylphosphino aryl fluorides as group electrophiles as the third in the donor reaction enable [27 the]. Inutilization order to of elucidate aryl fluorides the reactivity as electrophiles of the nickel(II)in the reaction complex [27 toward]. In order the relatively to elucidate robust the C-O reactivity bond in anof allylic the nickel(II) aryl ether, complex we herein toward describe the therelatively cross-coupling robust C- reactionO bond ofin allylican allylic ethers aryl with ether arylmagnesium, we herein describe reagents the usingcross- nickel(II)coupling reaction complexes of (allylic1a–d) ethers (Scheme with1). arylmagnesium reagents using nickel(II) complexes (1a–d) (Scheme 1).

Scheme 1. The coupling r reactioneaction of allylic ethers with aryl Grignard reagents using Ni(II)Ni(II) pincer complexes (1a1a–d).). 2. Results and Discussion 2. Results and Discussion 2.1. Optimization of the Reaction Conditions 2.1. Optimization of the Reaction Conditions 2.1.1. Initial Optimization of the Nickel(II) Complexes 2.1.1. Initial Optimization of the Nickel(II) Complexes To evaluate the catalytic activity of nickel(II) complexes 1a–d, we carried out the reaction between cinnamylTo evaluate phenyl ether the catalytic2a and 3 equivalentsactivity of of nickelp-tolylmagnesium(II) complexes bromide 1a–d, we3a using carried nickel(II) out the complexes reaction 1abetween–d (2.5 mol%)cinnamyl in THF phenyl at room ether temperature 2a and 3 (Table equivalents1), referring of p to-tolylmagnesium our previously study bromide on the3a biarylusing couplingnickel(II) reactioncomplex ofes aryl1a–d chlorides (2.5 mol%) with in arylmagnesium THF at room reagents temperature [26]. (Table Complex 1),1a referringgave the to linear our productpreviously4a studyin only on 7%the yield.biaryl coupling Complex reaction1b showed of aryl high chloride catalytics with activity arylmagnesium to give 4a reagentsin 86% yield. [26]. MoleculesMoleculesMoleculesMolecules 2019 20192019 2019, ,,24 24,24 24 FOR FORFOR FOR PEER PEERPEER PEER REVIEW REVIEWREVIEW REVIEW 333 3 Nickel(II)Complex 1a complexes gave the 1clineandar product1d bearing 4a Nin, Nonly,N- and7% yield.N,N,P C-typeomplex ligands 1b showed were not high catalytic activity to give 4aTableTableTableTable in 86 1. 1.1. 1. The% TheThe The yield. cross crosscross cross-- coupling-couplingN-couplingcouplingickel(II) reaction reactionreaction reaction complexes of ofof of cinnamyl cinnamylcinnamyl cinnamyl 1c and phenyl phenylphenyl phenyl 1d ether ether ether bearingether 2a 2a2a 2a with withwith with N p, pNp- -ptolylmagnesium-tolylmagnesium-tolylmagnesium,tolylmagnesiumN- and N,N, Pbromide bromidebromide -bromidetype ligands 3 33a a3a a were not effectiveusingusingusingusingTable Ni NiinNi Ni(II)(II) (II)t(II)he1. pincer pincerpincer pincerThe reaction cross-couplingcomplexes complexescomplexes complexes and ( (1 ( 1(1afforded))1.). ). a a. a areaction the of 2atargetwith product3a using Ni(II)in 2% pincer and complexes4% yield, (1respectively.). a In these cases, a large amount of 2a remained unreacted (see 2.3 Reaction mechanism section). In all cases, the branched product 5a was not detected and 4,4′-bitolyl (6a) derived from 3a was formed as a by-product (9–30%). In the absence of complex 1a–d, the reaction did not give any coupled products.

Ni cat 1 Yield of 4a (%) b Recovery of 2a (%) b

NNNNii i cati catcat cat 1 11 1 11a11a1aa a 111b1b1bb b 111c1c1cc c 111d1d1dd d 7 86 2 4 YYYieldYieldieldield of ofof of 4a 4a4a 4a (%) (%)(%) (%) b b b b 43777 7 88806866 6 28322 2 44904 4 RRaRecoveryRecoveryTheecoveryecovery reaction of ofof of 2a 2a2a was2a (%) (%)(%) (%) carried b b b b out using4443433 2a3 (0.5 mmol) and 3a000 (1.50 mmol) in the presence8883833 3 of 1 (0.0125 mmol,9990900 0 2.5 mol%) b 1 in THFaa a The aTheThe The (5 reaction mL) reaction reaction reaction for 24 was was was was h at carried carried carriedcarried room temperature.out out out out using using usingusing 2a 2a2a 2a ( (0.5( 0.5(0.5The0.5 mmol) mmol)mmol) mmol) yield and ofand andand4a 3a 3a3a and3a ( (1.5( 1.5(1.51.5 recovery mmol) mmol)mmol) mmol) in ofin inin 2a the the the thewere presence presence presence presence determined of of of of 1 1 1 1( (0.0125( 0.01250.0125( by0.0125H NMR analysis using pyrazine as the internal standard. mmolmmolmmolmmol,, , 2.5 ,2.5 2.52.5 mol% mol% mol%mol%)) ) in) in inin THF THFTHF THF ( (5( 55( 5mL) mL)mL) mL) for for forfor 24 2424 24 h hh h at atat at room roomroom room temperature. temperature.temperature. temperature. b b b Theb TheThe The yield yieldyield yield of of ofof 4a 4a 4a4a and and andand recovery recovery recoveryrecovery of of ofof 2a 2a 2a2a werewerewerewere determined determineddetermined determined by byby by 1 1H1 HH1H NMR NMRNMR NMR analysis analysisanalysis analysis using usingusing using pyrazine pyrazinepyrazine pyrazine as asas as the thethe the internal internalinternal internal standard. standard.standard. standard.

2.1.2.2.1.2.2.1.2.2.1.2. Investigation InvestigationInvestigation Investigation of ofof of the thethe the E EE ffectEffectffectffect of ofof of the thethe the S SS olventSolventolventolvent and andand and N NN Nickelickelickelickel(II)(II)(II)(II) C CC Complexesomplexesomplexesomplexes WeWeWeWe next nextnext next examined examinedexamined examined the thethe the solvent solventsolvent solvent effect effecteffect effect using usingusing using the thethe the reaction reaction reactionreaction between between betweenbetween 2a 2a 2a2a and andand and 3 33 3 equiv equivequiv equivalentsalentsalentsalents of ofof of 3a 3a3a 3a with withwith with complexcomplexcomplexcomplex 1 1 1b1bb.b. . The .The TheThe results results resultsresults are are areare summarized summarized summarizedsummarized in in inin Table Table TableTable 2. 2. 2.2. The The TheThe choice choice choicechoice of of ofof the the thethe solvent solvent solventsolvent used used usedused is is isis essential essential essentialessential to to toto produceproduceproduceproduce product product productproduct 4 44 a4aa a in inin in satisfactory satisfactorysatisfactory satisfactory yield. yield.yield. yield. When WhenWhen When cyclopentyl cyclopentylcyclopentyl cyclopentyl methyl methylmethyl methyl ether etherether ether (CPME) (CPME)(CPME) (CPME) was waswas was employed employedemployed employed as asas as solvent,solvent,solvent,solvent, the the thethe coupledcoupled coupledcoupled product product productproduct 4a 4a 4a4a was was waswas obtained obtained obtainedobtained in in inin 89% 89% 89%89% yield yield yieldyield (entry (entry (entry(entry 2). 2). 2).2). The The TheThe yield yield yieldyield of of ofof 4a 4a 4a4a decreased decreased decreaseddecreased in in inin 1,41,41,41,4--dioxane-dioxane-dioxanedioxane ( (71%,( 71%,(71%,71%, entr entr entrentryyy y 3). 3).3). 3). t t-t -Butylt-Butyl-ButylButyl methyl methylmethyl methyl ether etherether ether ( (MTBE( MTBE(MTBEMTBE)) ) and) andand and toluene toluenetoluene toluene were werewere were also also alsoalso effective effective effectiveeffective solvents solvents solventssolvents for for forfor thethethethe reaction reaction reaction reaction and andandand produced producedproducedproduced 4a 4a4a4a in ininin 82 828282%%%% and andandand 83%, 83%, 83%, 83%, respectively respectively respectively respectively (entries (entries(entries(entries 4 4 4 4 and and and and 5). 5). 5). 5). CH CH CH CH22Cl2Cl2ClCl22 2 2 and andandand NNNN,,N,NN,N--dimethylformamide-dimethylformamide-dimethylformamidedimethylformamide ( (DM (DM(DMDMFFF)F) ) were) were werewere not not notnot suitable suitable suitablesuitable for for forfor the the thethe reaction reaction reactionreaction (entries (entries (entries(entries 6 6 6 6 and and andand 7). 7). 7).7). Et Et EtEt22O2O2OO provided provided providedprovided thethethethe b bb estbestestest result, result,result, result, affording affordingaffording affording product productproduct product 4a 4a4a 4a in inin in 99% 99%99% 99% yield, yield,yield, yield, from fromfrom from which whichwhich which 4a 4a4a 4a was waswas was isolated isolatedisolated isolated in inin in 94% 94%94% 94% yield yieldyield yield ( (entr( entr(entrentryyy y 8 88 ).8).). ). TTTheThehehe other otherother other nickel nickelnickel nickel(II)(II)(II)(II) complexes complexescomplexes complexes 1a 1a1a 1a,, , 1c ,1c1c 1c,, , and ,andand and 1d 1d1d 1d exhibited exhibitedexhibited exhibited relatively relativelyrelatively relatively low lowlow low catalytic catalyticcatalytic catalytic activit activitactivit activity,y,y,y, even even eveneven in in inin Et EtEt Et22O2O2OO (entries(entries(entries(entries 99 9–9––1–11111).1).). ). WW WWhenhenhenhen the the the the amount amountamountamount of of of of Grignard GrignardGrignardGrignard reagent reagent reagent reagent 3a 3a3a3a used usedusedused was waswaswas reduced reduced reduced reduced to to to to 1.5 1.5 1.5 1.5 equivalents, equivalents, equivalents, equivalents, complexcomplexcomplexcomplex 1b 1b1b 1b acted actedacted acted as asas as an anan an effective effectiveeffective effective catalyst catalystcatalyst catalyst to toto to give givegive give 4a 4a4a 4a in inin in an anan an isolated isolatedisolated isolated yield yieldyield yield of ofof of 91% 91%91% 91% ( (entry( entry(entryentry 12). 12).12). 12).

Molecules 2019, 24, 2296 3 of 12 effective in the reaction and afforded the target product in 2% and 4% yield, respectively. In these cases, a large amount of 2a remained unreacted (see 2.3 Reaction mechanism section). In all cases, the branched product 5a was not detected and 4,40-bitolyl (6a) derived from 3a was formed as a by-product (9–30%). In the absence of complex 1a–d, the reaction did not give any coupled products.

2.1.2. Investigation of the Effect of the Solvent and Nickel(II) Complexes We next examined the solvent effect using the reaction between 2a and 3 equivalents of 3a with complex 1b. The results are summarized in Table2. The choice of the solvent used is essential to produce product 4a in satisfactory yield. When cyclopentyl methyl ether (CPME) was employed as solvent, the coupled product 4a was obtained in 89% yield (entry 2). The yield of 4a decreased in 1,4-dioxane (71%, entry 3). t-Butyl methyl ether (MTBE) and toluene were also effective solvents for the reaction and produced 4a in 82% and 83%, respectively (entries 4 and 5). CH2Cl2 and N,N-dimethylformamide (DMF) were not suitable for the reaction (entries 6 and 7). Et2O provided the best result, affording product 4a in 99% yield, from which 4a was isolated in 94% yield (entry 8). The other nickel(II) complexes 1a, 1c, and 1d exhibited relatively low catalytic activity, even in Et2O (entries 9–11). When the amount of Grignard reagent 3a used was reduced to 1.5 equivalents, complex 1b acted as an Moleculeseffective 2019 catalyst, 24 FOR to PEER give REVIEW4a in an isolated yield of 91% (entry 12). 4

a Table 2. SSolventolvent s screeningcreening using the reaction between 2a and 3a with complex 1.. a

EntryEntry Ni C Niat 1 Cat 1Solvent Solvent 4a4a (%) (%) b b EntryEntry Ni Ni C Catat 1 1S Solventolvent 4a4a (%)(%) bb 1 1 1b 1b THFTHF 86 86 77 1b1b DMFDMF 0 2 1b CPME 89 8 1b Et O 99(94) c 2 1b CPME 89 8 1b Et22O 99(94) c 3 1b 1,4-dioxane 71 9 1a Et2O 22 3 4 1b 1b 1,4-dioxaneMTBE 71 82 109 1a1c EtEt22OO 1922 5 1b toluene 83 11 1d Et O 30 4 1b MTBE 82 10 1c Et22O 19 d c 6 1b CH2Cl2 24 12 1b Et2O 95(91) 5 1b toluene 83 11 1d Et2O 30 a The reaction was carried out using 2a (0.5 mmol) and 3a (1.5 mmol) in the presence of 1 (0.0125 mmol, 2.5 mol%) in b 1 6solvent (5 mL)1b for 24 h at roomCH2Cl temperature.2 The24 yield of 4a was12 determinedd 1b by H NMR analysisEt2O using pyrazine95(91) c as the internal standard. c Isolated yield. d 0.75 mmol of 3a was used. a The reaction was carried out using 2a (0.5 mmol) and 3a (1.5 mmol) in the presence of 1 (0.0125 mmol, 2.5 mol%) in solvent (5 mL) for 24 h at room temperature. b The yield of 4a was determined by 2.1.3. Investigation of the Effect of the Leaving Group on the Allylic Electrophile 1H NMR analysis using pyrazine as the internal standard. c Isolated yield. d 0.75 mmol of 3a was used.In order to investigate the influence of the leaving group (LG) on the allylic substrate, we carried out the reaction between various cinnamyl electrophiles (2a–d, 7, and 8) with 1.5 equivalents of 3a in 2.1.3.the presence Investigation of 1b (2.5of the mol%) Effect in of Et the2O L (Tableeaving3). G Cinnamylroup on the phenyl Allylic ether Electrophile2a was converted into 4a in 91%In isolated order yield. to investigate In the case the of influence cinnamyl ofp-methoxyphenyl the leaving group ether (LG)2b, the on cross-coupled the allylic substrate, product we4a carriedwas isolated out the in reaction excellent between yield (96%). various When cinnamyl the amount electrophiles of nickel(II) (2a complex–d, 7, and1b 8used) with was 1.5 reducedequivalents to 1 mol%, 2a was converted into 4a in 60% yield, whereas in the case of 2b, product 4a was isolated in 95% of 3a in the presence of 1b (2.5 mol%) in Et2O (Table 3). Cinnamyl phenyl ether 2a was converted inyield.to 4a The in 91% reaction isolated of cinnamyl yield. In ether the case2c bearing of cinnamyl a p-trifluoromethylphenyl p-methoxyphenyl ether group 2b in, the the cross leaving-coupled group productafforded 4a4a wasin 62% isolated yield. pin-Methoxyphenoxide, excellent yield (96%). which When has the an electron-donatingamount of nickel group(II) complex on the aromatic1b used wasring, reduced acted as to an 1 emol%,ffective 2a leaving was converted group. Methyl into 4a ether in 60%2d yield,was also whereas applicable in the in case the of reaction 2b, product using 4a2.5 was mol% isolated of 1b to in give 95% product yield. The4a in reaction 90% yield. of cinnamyl When 1 mol%ether 2c of 1bbearingwas employed,a p-trifluoromethylphenyl the product was groupobtained in inthe 73% leaving yield. Cinnamyl group afforded alcohol 4a7 was in also 62%able yield. to bep- usedMetho asxypheno an electrophile,xide, which however, has the an electronyield of-4adonatingwas low group (40%) on and the7 wasaromatic recovered ring, inacted 54%. as In an the effective case of leaving cinnamyl group. chloride Methyl8, compound ether 2d was4a was also formed applicable in low in yieldthe reaction (38%). using 2.5 mol% of 1b to give product 4a in 90% yield. When 1 mol% of 1b was employed, the product was obtained in 73% yield. Cinnamyl alcohol 7 was also able to be used as an electrophile, however, the yield of 4a was low (40%) and 7 was recovered in 54%. In the case of cinnamyl chloride 8, compound 4a was formed in low yield (38%).

Molecules 2019, 24 FOR PEER REVIEW 5

Molecules 2019Molecules, 24 FOR 2019 PEER, 24 FORTableREVIEW PEER 3. TheREVIEW effect of the leaving group (LG) on the cinnamyl electrophiles. 5a 5 Molecules 2019, 24 FOR PEER REVIEW 5 Table 3. TheTable effect 3. The of the effect leaving of the group leaving (LG) group on the (LG) cinnamyl on the cinnamylelectrophiles electrophiles. a . a MoleculesMolecules 2019Molecules2019, 24, 24FOR ,2019 2296 PEER, 24 FORREVIEW PEER REVIEW 5 4 of5 12 Molecules 2019, 24 FORTable PEER REVIEW3. The effect of the leaving group (LG) on the cinnamyl electrophiles. a 5 Table 3. TheTable effect 3. Theof the effect leaving of the group leaving (LG) group on the (LG) cinnamyl on the electrophilescinnamyl electrophiles. a . a Table 3. The effect of the leaving group (LG) on the cinnamyl electrophiles. a Table 3. The effect of the leaving group (LG) on the cinnamyl electrophiles. a

b b c 2a, 91%b , 60% b 2b,b 96%, 95%b c 2cc, 62% 2a, 91%, 260%a, 91% , 60% 2b, 96%, 295%b, 96% , 95% 2c, 62% 2c, 62%

2a, 91%, 60% b 2b, 96%, 95% b 2c, 62% c b b b b c c 2a, 91%, 60%2a, 91% , 60% b 2b, 96%, 95%2b, 96% , 95% b 2c, 62% 2c, 62% c 2a2,a 91%, 91%, 60% , 60% b 2b, 96%2b, , 96%95%, b 95% 2c, 62% c2 c, 62% 2d, 90% c, 73% b 7, 40% c,d 8, 38% c a c b c b c,d c,d c c The reaction2d, 90% was 2, d73% carried, 90% c out, 73% using b the cinnamyl7, 40% electrophile 7 , 40% (2, 7c,,d8 (0.5 mmol)),8 and, 38%3a (0.75 8, 38% mmol) inthe c presence of 2d, 90% , 73% 7, 40% b 8, 38% c 1b (0.0125 mmol, 2.5 mol%) in Et 2O (5 mL) for 24 h at room temperature. Isolated yield. 1 mol% of 1b was used. The a a 1 d yieldThe reactionofa 4a Thewas was determinedreaction carried was by out carriedH using NMR out the analysis using cinnamylusing the cinnamyl pyrazineelectrophile aselectrophile the (2, internal 7, 8 (0.5 ( standard.2, mmol)7, 8 (0.5), 1.25andmmol) mmol3a )(, 0.75and of 3a 3awas (0.75 used. 2 dThe, 90% reaction c,2 73%d, 90% b was c, 73% carried b out7 ,using 40% c ,dthe 7, 40%cinnamyl c,d electrophile8, 38% (2, c7 , 8 8, 38%(0.5 cmmol) ), and 3a (0.75 mmol) in mmol)the presence in the cofpresence 1b (0.0125b of 1b mmol (0.0125, 2.5 mmol mol%, )2.5 in c mol%,Etd 2O ()5 in mL) Et2 Ofor ( 524 mL) h at for room 24 h temperature. at roomc temperature. 2d, 90% , 73%c b 7, 40% c,d 8, 38% c mmol) b2ind ,the 90% presenceb , 73% of 1b (c0.0125 mmolc 7, , 2.540% mol% ) in Et2O 1(5 mL) for1 24 h8 ,at 38% room temperature. aIsolated yield.Isolateda 1 mol%yield. of 1 1b mol% was of used. 1b was The used. yield Theof 4a yield was ofdetermined 4a was determined by H NMR by analysisH NMR using analysis using 2.2. SubstrateThe reaction The Scope was reaction carriedb was out carried using outthe usingcinnamyl the c cinnamylelectrophile electrophile (2, 7, 8 (0.5 (2 ,mmol) 7, 8 (0.5), and mmol) 3a1 )(,0.75 and 3a (0.75 pyrazineaIsolated The aspyrazine the reaction internal yield. as the was standard. 1internal mol% carried standard.d of out1.25 1b using mmolwas d 1.25used. theof 3a mmolcinnamyl was The ofused yield3a electrophile .was of used 4a was. (2 , determined7, 8 (0.5 mmol) by ),H and NMR 3a (analysis0.75 using a 2 2 mmol) in Themmol)the presence reaction in the ofpresence was 1b (0.0125 carried of 1b mmol out(0.0125 , using2.5d mmolmol% the, )2.5 incinnamyl Etmol%O ()5 inmL) electrophileEt forO ( 524 mL) h at for room(2 ,24 7 , h temperature. 8at ( 0.5room mmol) temperature. ), and 3a (0.75 mmol)pyrazine in the as thepresence internal of 1b standard. (0.0125 mmol 1.25, 2.5 mmol mol% of) 3ain Etwas2O (used5 mL). for 24 h at room temperature. IsolatedWith theyield.Isolated optimized b 1 mol% yield. ofbconditions 1 1b mol% was ofused. 1b in wasc hand,The used. yield we c Theof next 4a yield was examined ofdetermined 4a was thedetermined by substrate 1H NMR by analysis 1 scopeH NMR ofusing analysis the reaction using using mmol) in theb presence of 1b (0.0125c mmol, 2.5 mol%) in Et2O (5 mL)1 for 24 h at room temperature. 2.2. Substrate2.2.Isolated Substrate Scope yield. Scope 1 mol% of 1bd was used.d The yield of 4a was determined by H NMR analysis using allylicpyrazine ethers aspyrazine2 thebearing internal as the a bstandard.p internal-methoxyphenoxide standard. 1.25 mmol 1.25 of 3a mmol group wasc usedof as3a. the was leavingused. group and a range1 of arylmagnesium 2.2. SubstratepyrazineIsolated asyield. S thecope internal 1 mol% standard. of 1b wasd 1.25 used. mmol ofThe 3a yieldwas used of 4a. was determined by H NMR analysis using reagentsWith (the3pyrazine)With inoptimi the the presenceaszed optimithe conditions internalz ofed 1conditions mol%standard. in hand, of 1bindwe 1.25 hand,as next themmol weexamined catalyst ofnext 3a examinedwas (Tablethe used substrate4).. the The substrate scope reaction of scopethe of cinnamylreaction of the reaction ether 2b 2.2. Substrate2.2. SubstrateScope Scope usingwith 2.2. phenylmagnesiumallylicusing SubstrateWith ether allylic thes S 2cope optimietherbearing s bromide 2z edabearing p -conditionsmethoxyphe3b a gavep-methoxyphe in thenoxide hand, coupled group noxidewe productnext as group the examined leaving4b as inthe excellent groupleavingthe substrate and groupyield a range (94%)andscope ofa with rangeof the linear of reaction arylmagnesiumselectivity.With2.2.usingarylmagnesium theSubstrate allylic WithInoptimi reagent the the Sz caseetheredcope optimis reagentconditions(3of s) in2 4-methoxyphenylmagnesiumz edbearingthes (conditions 3presence )in in hand, thea p presence -of methoxypheinwe 1 hand, mol%next of examined we of1 mol% 1bnextnoxide as bromide examinedtheof the 1b catalyst group substrate as the3c the , ( ascatalystTable which substrate scopethe 4 ). leaving( has TableofThe scopethe anreaction 4 reaction). electron-donating group Theof the ofreaction andreaction a of range of With the optimized conditions in hand, we next examined the substrate scope of the reaction usingcgroupinnamyl allylicarylmagnesium oncusing innamyl ether theether allylic 2 aromaticb s ether with2 bearingether reagent2 phb ring,s e withnyl2 abearing magnesp the ph-(methoxyphe3)e couplednylin sai um themagnep-methoxyphe bromidepresencenoxide productsium bromide 3b groupofnoxide 4c gave1 mol%was as 3b the groupthe isolatedgave of coupled leaving 1b as the asthe in coupled productthe groupleaving 94% catalyst yield. and product4b group in a( Tablerangeexcellent The and4b reactionin4 ofa). excellent rangeThe reaction withof of using allylic ethers 2 bearing a p-methoxyphenoxide group as the leaving group and a range of arylmagnesiumyield4-N,N (94%-dimethylaminophenylmagnesiumyieldarylmagnesium)With with ( 94%reagent thelinear) with optimis selectivity. reagent( 3linear) inz edthe sselectivity. (conditionspresence3 In) in the the case presence of bromideIn 1 in the ofmol% hand, 4 case- methoxyphenylmagneof3d of 1 ofwe1bmol%gave 4 as-nextmethoxyphenylmagne producttheof 1bexaminedcatalyst as 4dthe ( siinTablecatalystum 95%the bromide 4 substrate). yield. (si TableTheum reactionbromide We 3c4)., scope recentlyThe which ofreaction 3c of, whichreported the of reaction carylmagnesiuminnamyl ether reagent 2b withs (3 ) phin ethenyl presencemagnes iofum 1 mol% bromide of 1b 3bas thegave catalyst the coupled(Table 4). productThe reaction 4b ofin excellent chasinnamyl anusing electronhasc innamyl ether anallylic -2electrondonatingb etherwith ether - phdonating2 groupbs e withnyl2 bearingmagne on phgroup theenyls iumaromaticamagne on p - bromidemethoxyphethes iaromatic umring, bromide3b the gave ring,noxidecoupled the3b the gave coupled groupcoupledproduct the as productcoupledproduct4c the was leaving isolated4b product4c inwas excellent group inisolated4b 94% in excellent and in 94% a range of that complexesyieldcinnamyl (94% ether1b) withand 2b 1dwithlinearact ph asselectivity.e annyl effectivemagne sInium catalyst the bromide case for of the3b 4 gave- cross-couplingmethoxyphenylmagne the coupled reaction product ofsi 4bum aryl in bromide fluoridesexcellent 3c with, which yieldyield. (arylmagnesium94%Theyield.yield ) reactionwith (The94% linear ) reactionwith with selectivity.reagent 4linear-N with,N- dimethylaminophenylsselectivity. ( 4 3In-N) in, theN -thedimethylaminophenyl case Inpresence theof 4 case-methoxyphenylmagne magnesof of 1 4mol%-methoxyphenylmagneiummagnes of bromide 1bium assi bromidetheum3d gavecatalystbromidesi um3d product gave (bromide3cTable, which product4d 4 in ).3c The, which4d reaction in of arylmagnesiumhasyield an (94% electron) reagentswith -lineardonating [27 selectivity.]. Ingroup the reaction Inon the the case witharomatic of 4-fluorophenylmagnesium4-methoxyphenylmagne ring, the coupled siproductum bromidebromide 4c was 3e3c, productisolatedwhich 4ein 94% has95% an yield.c electroninnamyl95%has We an yield.- donatingelectron recently ether We 2- donating recentlyb reportedgroup with on phreportedgroup thattheenyl aromatic complexes onmagne that the aromaticcomplexessring,i um1b theand bromide ring,coupled 1d1b theactand 3b productcoupled a 1dsgave an act effective the4c aproducts was an coupled effectiveisolated catalyst 4c was product in catalystforisolated 94% the 4b forin in 94% the excellent was obtainedyield.hascross an Theelectron-coupling in 96%reaction-donating yield. reaction with In group ofthe 4 - arylN present ,onN fluorides- dimethylaminophenylthe reactionaromatic with conditions, ring, arylmagnesium the coupledmagnes the reaction reagents productium bromide of [4c274e ].was asIn an isolated the3d electrophile reactiongave in product94% with with 4d in yield.cross- couplingyieldTheyield. reaction (94% The reaction) with reaction of 4linear- N aryl with,N- dimethylaminophenyl fluoridesselectivity. 4-N,N-dimethylaminophenyl with In aryl themagnesium casemagnes of i4ummagnes -methoxyphenylmagnereagents bromideium [27 bromide3d]. Ingave the product3d reaction gavesium 4d product withbromide in 4d 3cin, which Grignardyield. reagent The reaction3e did with not 4 occur.-N,N-dimethylaminophenyl In cases of stericallymagnes congestedium bromide arylmagnesium 3d gave product reagents, 4d suchin as 95%4-fluorophenyl yield.95%495%- fluorophenyl We yield. yield. magnesium recently We We magnesium recently recentlyreported bromide reported reported that bromide3e , complexes product that that3e ,complexes product complexes4e1b wasand 4eobtained1d1b was act1band aand obtained s1din an act 96%1d effective a acts yield.in an 96% a s effective catalyst Inan yield. the effective forpresent catalyst In thethe catalyst present for the for the has95% an yield. electron We recently-donating reported group that on complexesthe aromatic 1b ring,and 1d the act coupled as an effectiveproduct catalyst4c was forisolated the in 94% crossreaction1-naphthylmagnesium-couplingcross reactioncrossconditions-coupling- coupling reaction conditions, the reaction reactionof bromide aryl, the fluorides reactionof of 3f 4e aryl aryl, oas-tolylmagnesium fluoridesanof withfluorides 4eelectrophile as aryl an withmagnesium electrophile with arylwith bromide arylmagnesium Grignard magnesiumreagents with3g Grignardand reagent reagents [27 2,4,6-trimethylphenylmagnesium]. reagents In 3ereagent the [did27 ]. reaction notIn [3e27 the occur.].did In reactionwithnot theIn occur. reaction with In with yield.cross-coupling The reaction reaction with of aryl 4-N fluorides,N-dimethylaminophenyl with arylmagnesiummagnes reagentsium [27 bromide]. In the 3d reaction gave productwith 4d in 4casesbromide-fluorophenyl of4- fluorophenylcases4sterically-3hfluorophenyl, theofmagnesium sterically correspondingcongestedmagnesiummagnesium congested bromide arylmagnesium products bromide bromide3e aryl, productmagnesium4f ,3ereagents 4g3e, ,product,4e andproduct was ,reagents 4hsuch were obtained4e as4ewas, 1suchobtained -wasnaphthyl obtained in as obtained96% 1- innaphthylmagnesium 85%, yield. in 96% 79%,in magnesium In yield.96% thebromide and present yield. 80%,In bromidethe3f respectively,, In present the 3f , present 95%4-fluorophenyl yield. Wemagnesium recently bromide reported 3e that, product complexes 4e was 1b obtained and 1d in act 96% as yield. an effective In the present catalyst for the reactionoin-tolylmagnesium thereaction presence conditionsoreaction-tolylmagnesium conditions ofconditions bromide, 2.5the mol% reaction bromide,3g, thethe of and 1bofreaction 2,4,64eunder 3g as and- trimeth anof refluxingof 2,4,6electrophile4e 4e asylphenyl -astrimeth an an conditions.electrophile electrophile ylphenylwithmagnesium Grignard Themagnesiumwith bromidewithreaction Grignard reagent Grignard bromide3h of 3e ,reagent pthe -substituteddid corresponding reagent3hnot 3e, theoccur. did corresponding 3e cinnamylnot In did occur. not etherIn occur. In crossreaction-coupling conditions reaction, the reaction of aryl of 4e fluorides as an electrophile with aryl withmagnesium Grignard reagentsreagent 3e [ 27did]. notIn occur. the reaction In with casesproducts2i, which ofcases stericallyproductscases 4f has, of4g of an,sterically andsterically electron-donating4fcongested, 4h4g , wereand congestedcongested aryl 4hobtained magnesiumwere group aryl arylobtained inmagnesium 85%,magnesium (OMe) reagents 79in %85%, on, and,reagents thesuch 79reagents 80%, aromatic% as, and, 1respectively,such-naphthyl , 80%,such ring, as respectively,1 - withasnaphthylmagnesium 1in-p naphthylthe-tolylmagnesium magnesiumpresence in bromide themagnesium presence of bromide3f2.5, bromide of bromide 2.53f, 3a 3f, cases of sterically congested arylmagnesium reagents, such as 1-naphthylmagnesium bromide 3f, omol%-tolylmagnesium 4of-fluorophenyl mol%o1b-tolylmagnesium under 4iof 1bbromide reflux undermagnesiuming bromide3greflux conditions. anding 2,4,6 3g bromideconditions. -andtrimeth The 2,4,6 reaction ylphenyl3e- trimethThe, product reactionof magnesiumylphenylp-substituted2j 4eof magnesiumpwas-substituted bromide cinnamyl obtained bromide3h cinnamyl ,ether the in corresponding 2i3h 96%, ,etherwhich the yield. corresponding 2i has, which In the has present gaveo product-tolylmagnesiumtolylmagnesiumin 78% bromide yield. bromide In 3g the and3g case and 2,4,6 of 2,4,6- electrophiletrimeth-trimethylphenylylphenylbearingmagnesiummagnesium an electron-withdrawing bromide bromide 3h, the corresponding 3h, the group corresponding (F), the productsan electronreaction anproducts4f -,electron donating4g ,conditions and 4f-, donating 4h4ggroup ,were and, (OMe)the 4hobtainedgroup reactionwere on (OMe) obtainedthein of85%,aromatic on 4e the 79asin% 85%,anaromatic ,ring, and electrophile 79 with80%,% ,ring, and prespectively,-tolylmagnesium with80%, with prespectively,- tolylmagnesiumGrignard in the bromide presence reagentin the bromide3a presenceof 3egave 2.5 did 3a ofnot gave 2.5 occur. In coupledproducts product 4f 4f, ,4g4j 4g,was and, and obtained4h 4h were were obtained in 89%obtained yield. in 85%, in In 85%,79 the%, coupling 79and% ,80%, and reaction,respectively, 80%, respectively, alkyl- in andthe presence benzylmagnesium in the presenceof 2.5 of 2.5 mol%product casesof productmol%4i1b in underof 78% ofsterically 4i1b refluxyield. in under 78%ing In congested refluxyield. theconditions. case ingIn theofconditions. aryl electrophile Thecasemagnesium reaction of electrophileThe 2j ofreaction bearing preagents-substituted 2j of anbearing p -,electronsubstituted such cinnamyl an as -electronwithdrawing 1 -cinnamyl naphthylether-withdrawing 2i, etherwhichgroupmagnesium 2i has(F),, whichgroup bromide has(F), 3f, reagentsmol% were ofof 1b 1b not under under suitable reflux reflux asing nucleophiles.ing conditions. conditions. The In reactionThe addition, reaction of p the-substituted of reaction p-substituted cinnamyl using acinnamyl cisether/trans 2i, mixtureetherwhich 2ihas, ofwhich 2b0 has anthe electron coupledo-tolylmagnesiumthean- donating electron coupled product-donating group product4j bromidewas (OMe) group 4j obtained onwas 3g(OMe) the and obtained aromatic in on2,4,6 89% the- trimeth inaromaticring, yield. 89% with ylphenyl In yield.ring, thep-tolylmagnesium withcouplingInmagnesium thep-tolylmagnesium coupling reaction, bromide reaction, alkyl bromide3a 3h- gave, andthe alkyl 3acorresponding- gaveand (cis:transan benzyl electronelectron= 86:14)magnesium-donating- withdonating Grignard groupreagents group (OMe) reagent were(OMe) on not3a theonafforded suitable aromaticthe aromatic the as ring, nucleophiles.trans withring,product p with-tolylmagnesium In (4a p addition,-)tolylmagnesium in 88% theyield bromide reaction as a bromide3a sole usinggave product a3a gave productbenzylproductsmagnesium 4iproduct in 78% 4f4i yield., reagents in4g 78%, andIn yield. thewere 4h case were In not ofthe suitableelectrophileobtained case of aselectrophile innucleophiles. 2j 85%, bearing 79 2j % anbearing , Inandelectron addition, 80%, an- withdrawingelectron respectively, the reaction-withdrawing group usingin the(F), group a presence (F), of 2.5 product 4i in 78% yield. In the case of electrophileγ 2j bearing an electron-withdrawing2g group (F), thecis(Table/ trans coupledproduct5 ,mixturecisthe entry/ trans coupled product 4i 1). ofmixture in In2b’ 78% contrast product(4jcis of :wastransyield. 2b’ to (= obtained4jcis 86:14) cinnamylIn:transwas the with= obtainedcase 86:14) in ethers,Grignard89% of with electrophile in yield. Grignard-alkyl 89%reagent In yield. substitutedthe 3areagent2j afforded bearingcouplingIn the3a allylic affordedthe couplingan r eaction, transelectron ether theproduct r eaction,trans a-lkylwithdrawingafforded -(product 4aand ) ainlkyl a (-mixture4a and )group in (F), mol%the coupled of 1b under product reflux 4j wasing conditions. obtained in The 89% reaction yield. Inof pthe-substituted coupling cinnamyl reaction, aetherlkyl- 2iand, which has benzyl88%of the yieldthemagnesium linear88%benzyl as coupled yield a and magnesiumsole reagents branched as product product a sole reagents wereproduct ( isomersTable 4j not was 5, were ( suitableTable (entry4k obtainedand not 5,1). assuitable entry5kIn nucleophiles.)contrast in in1 96%). asIn 89% nucleophiles.contrastto yield. cinnamyl yield. In The addition,to cinnamyl ratioIn ethers, In the addition, of the γ4k couplingethers,- reactionalkyl:5k thewas substitutedγ -alkyl reactionusing determined reaction, substituted a using alkyl to a be- and anbenzyl electronmagnesium1 -donating reagents group were (OMe) not suitableon the aromatic as nucleophiles. ring, with In addition, p-tolylmagnesium the reaction bromideusing a 3a gave cisallylic54:46/trans benzyl usingether mixtureallyliccis/ trans2gmagnesiumH affordedether NMRofmixture 2b’ 2g (spectroscopy cisaffordeda ofmixture: trans reagents2b’ (= cisa 86:14) ofmixture:trans the (entrywere with linear= 86:14)of 2). notGrignardthe and These withlinear suitable branch Grignard results reagentand ed asbranch isomers indicate nucleophiles.3a reagent affordeded (isomers4k that 3a and affordedthe the 5k( Intrans4k reaction) in addition,and theproduct96% 5k transproceeds )yield. in (96%product the4a The) in reactionyield. via ( a4a πThe) -allylin using a productcis/trans mixture 4i in 78% of 2b’ yield. (cis:trans In the = 86:14) case withof electrophile 1Grignard1 reagent 2j bearing 3a afforded an electron the trans-withdrawing product (4a) in group (F), 88%rationickel yield ofcis intermediateratio88%4k/trans as:5k ayield of wasmixturesole 4k as: determined5kproduct (vide a was soleof 2b’ infra). determined (productTable (tocis : beTherefore,trans 5, (Tableentry54:46 to = 86:14) be 1using5,). we54:46entryIn withcontrast examinedH using1 ).NMR GrignardIn tocontrast Hspectroscopy thecinnamyl NMR reaction reagent to spectroscopy cinnamyl ethers, ( usingentry3a affordedγ -ethers, alkyl secondary2 )(.entry These substituted γ the -alkyl 2 ) results. trans allylicThese substituted product resultsethers as(4a) in the88% yieldcoupled as a productsole product 4j (wasTable obtained 5, entry 1 ). inIn contrast 89% yield. to cinnamyl In the ethers, coupling γ-alkyl r eaction,substituted alkyl - and allylicindicateelectrophiles. 88%ether indicateallylic that yield2g the affordedether The that reactionas reaction2g a the soleaffordeda mixture reaction proceeds product of ana of mixture proceeds allylicthe via ( Table lineara of etherπ - the viaallyl and 5, linear bearingentrya branchnickelπ-allyl and 1 ).ed intermediate a nickelbranchIn phenylisomers contrast intermediateed group (isomers4k (vide toand atcinnamyl 5k infra)( the4k )(vide inandα . 96%-position Therefore, 5k infra)ethers, yield.) in. 96% Therefore, (The2h γ we- alkylyield.) proceeded substitutedThe we examinedbenzylallylicexamined the ethermagnesium reaction 2g the afforded reactionusing reagents secondary a using mixture secondarywere allylic of the not etherslinear allylic suitable1 asand ethers electrophiles. branch as1 as nucleophiles. electrophiles.ed isomers The reaction (4k T In heand addition,ofreaction 5kan) allylicin 96%of thean ether yield. allylic reaction The ether using a ratiowith of linear 4kratio:5k selectivity ofwas 4k : determined5k was to afford determined to product be 54:46 to 4a beusing as54:46 a singleH using NMR regioisomer Hspectroscopy NMR spectroscopy in high(entry yield 2 ).( entryThese (94%). 2 ) results. InThese this results reaction, allylicratio of ether 4k:5k 2g was afforded determined a mixture to be of54:46 the linearusing 1andH NMR branch spectroscopyed isomers (entry (4k and 2). These5k) in results 96% yield. The indicatebearingcis abearingindicate that/ transphenyl the mixture a group thatreaction phenyl the atof group reactionthe proceeds 2b’ α (- positioncisat the: proceedstrans via α - a position(= 2hπ 86:14)- )allyl viaproceeded a( nickel2hwithπ)- allylproceeded Grignardwith intermediate nickel linear with intermediate reagent selectiv linear(vide ity3a selectiv infra) toafforded(vide afford. ity Therefore, infra) to product theafford. Therefore,trans we 4aproduct product we4a (4a) in branchedratioindicate isomer of that4k: 5k5a the waswas reaction not determined detected proceeds (entry to via be a 3). 54:46π- Inallyl contrast, using nickel 1 an intermediateH allylicNMR etherspectroscopy (vide bearing infra)an .( entry Therefore, alkyl group2). These we at the results examinedas a single88%asexamined the regioisomera yield singlereaction asthe regioisomer a usingreaction solein high secondaryproduct using yieldin high secondary(94%). (allylicTable yield In ethers(94%).5, thisallylic entry reaction,as In etherselectrophiles. this1). In reaction,asbranch contrast electrophiles. edT hebranch isomer toreaction cinnamyled T he5a isomer ofreactionwas an not ethers,allylic5a ofwasdetected an ether γnot allylic-alkyl detected ether substituted α-positionindicateexamined (2i ) that wasthe reaction converted the reaction using into secondary proceeds a mixture allylic via of regioisomers aethers π-allyl as electrophiles. nickel (4k and intermediate5k T)he in reaction 93% yield.(vide of an The infra) allylic ratio. ether Therefore, of 4k :5k we bearingallylic abearing phenyl ether agroup phenyl 2g afforded at groupthe α- positionata mixturethe α -(position2h of) proceeded the ( 2hlinear) proceeded with and linear branch with selectiv edlinear isomersity selectiv to afford (4kity andtoproduct afford 5k) 4ainproduct 96% yield.4a The was determinedexaminedbearing a phenyl the to bereaction group 57:43 usingat using the 1α H-secondaryposition NMR spectroscopy (2h allylic) proceeded ethers (entry with as electrophiles. 4).linear The selectiv reactionity The ofto areactionafford mixture product of of an2j 4aallylicand 2k ether as a singleratioas regioisomer a of single 4k:5k regioisomer wasin high determined yield in high (94%). yield to In be(94%). this 54:46 reaction, In using this reaction,branch 1H NMRed branch isomer spectroscopyed 5a isomer was not 5a ( detectedwasentry not 2 )detected. These results (2j:2kbearingas= a67:33) single a gave phenylregioisomer the lineargroup in product highat the yield α4l-position in(94%). 90% In yield(2h this) withproceeded reaction, high branch regioselectivity. with edlinear isomer selectiv The5a was branchedity not to detectedafford isomer product (5l) 4a indicate that the reaction proceeds via a π-allyl nickel intermediate (vide infra). Therefore, we was notas a detected single regioisomer (entry 5). The in regioselectivity high yield (94%). in this In reaction this reaction, probably branch dependsed isomer on both 5a maximizing was not detected the examined the reaction using secondary allylic ethers as electrophiles. The reaction of an allylic ether resonance stabilization energy on the coupling product and minimizing steric hindrance in the coupling of bearing a phenyl group at the α-position (2h) proceeded with linear selectivity to afford product 4a the Grignard reagent with the putative π-allyl nickel species [13]. In the reaction of the γ-alkyl substituted as a single regioisomer in high yield (94%). In this reaction, branched isomer 5a was not detected allylic ether, the steric influence should operate predominantly for the formation of the product.

Molecules 2019, 24 FOR PEER REVIEW 6

(entry 3). In contrast, an allylic ether bearing an alkyl group at the α-position (2i) was converted into Moleculesa mixture 2019 of, 24 regioisomers FOR PEER REVIEW (4k and 5k) in 93% yield. The ratio of 4k:5k was determined to be 57:436 Moleculesusing 12019H MoleculesNMR, 24 FOR spectroscopy PEER2019, 24REVIEW FOR PEER (entry REVIEW 4). The reaction of a mixture of 2j and 2k (2j:2k = 67:33)6 gave the6 (entrylinear product3). In contrast, 4l in 90% an ayieldllylic withether high bearing regioselectivity an alkyl group. The at branched the α-position isomer (2i ()5l was) was conve not rteddetected into (entry 3). In(entry contrast, 3). In an contrast, allylic ether an a llylicbearing ether an bearingalkyl group an alkyl at the group α-position at the (α2i-position) was conve (2i)rted was intoconve rted into Molecules 2019, 24 FOR PEER REVIEW 6 aMoleculesa( entrymixture mixture 20195 ).ofMoleculesa ,The of 24mixtureregioisomers FORregioisomers regioselectivity 2019PEER of, 24 REVIEWregioisomers FOR (4k PEER (and 4k REVIEWandin5k )this( 4k in5k 93and )reaction %in 5k yield93) %in . probablyyield93The% ratioyield. The .ofdepends Theratio 4k :ratio5k of was on4kof :4kdeterminedboth5k:5k was maximizingwas determined determined to be 57:43 the 6 toto resonance be 57:436 usingusingstabilization 1 H1H NMR usingNMR energyspectroscopy 1 Hspectroscopy NMR on spectroscopythe (entry coupling (entry 4). The (entry4). product reaction The 4). reaction The and of reactiona minimizingmixture of a ofmixture of a mixture2j stericand of 2k 2j ofhindra ( 2jand2j: 2kand 2k=nce 2k67:33) ( 2j in(2j:2k the: 2kgave = = coupling67:33) 67:33) the gave of thethe (entry(entryMolecules 3). 3). In 2019(entry In contrast, ,contrast, 24 3).FOR In anPEER contrast, aanllylic REVIEW allylic ether an aether llylicbearing bearingether an bearingalkyl an groupalkyl an alkyl atgroup the group α at-position theat the α- positionα(2i-position) was conve ( 2i(2i) )was rtedwas conveintoconve rtedrted 6into into linearMoleculeslinearGrignard product product2019Moleculeslinear , 24 reagent FOR4l 4linproduct PEER2019 90%in with,90% 24REVIEW yield FOR4l yieldin the PEER with 90% putative withREVIEW highyield highregioselectivity with π regioselectivity -highallyl regioselectivity nickel. The speciesbranched. The. The branched [13]. isomer branched In ( 5lisomer the) isomerwas reaction not (5l (5l )detected )was was of notnot6 the detected γ-alkyl6 aa mixture mixture ofa of mixtureregioisomers regioisomers of regioisomers (4k (and4k and5k ()4k in 5k and93) %in 5k yield93) %in. 93yieldThe% yieldratio. The . ofThe ratio 4k ratio:5k of was of4k 4k:determined5k:5k was was determined determined to be 57:43 to bebe 57:4357:43 ((entrysubstitutedentry 5 ).5 ).The (Theentry allylicregioselectivity regioselectivity 5). Theether, regioselectivity the in stericthis in thisreaction influence in reaction this probably reaction should probably depends probably operate depends on depends predominantlyboth onmaximizing onboth both maximizing maximizing forthe theresonance formation the the resonanceresonance of the using(entry 1H1 3).NMRusing In contrast, spectroscopy 1H NMR an spectroscopy a llylic(entry ether 4). The (entrybearing reaction 4). an The ofalkyl reactiona mixture group of ofata mixture 2jthe and α- position2k of ( 2j: 2kand (=2i 2k67:33)) was (2j: 2k gaveconve = 67:33) therted gave into the stabilization(entryusing 3). H In (entrystabilizationNMR contrast, energy 3). spectroscopy onIn an contrast, the energyallylic coupling etheron an (entry the a llylicbearingproduct coupling 4). ether The anand bearingproductalkyl reactionminimizing group an and alkylof at minimizing a stericthe mixture group α -hindraposition at stericofthence 2j α(2i -inandhindraposition) wasthe 2k coupling convence ( 2j(2i in:2k) rtedwasthe =of 67:33) couplinginto convethe rtedgave of into the the linearstabilizationproduct.a mixture product linear of energy4l regioisomers productin 90% on yield 4l the in ( with90%4kcoupling and yieldhigh 5k regioselectivitywithproduct) in 93high% andyieldregioselectivity minimizing.. TheThe branchedratio. Theof steric 4k isomerbranched:5k hindra was (5l ) isomer determinedwasnce notin ( 5lthe detected) was coupling to notbe 57:43detected of the Grignardalinear mixture product of reagenta mixtureregioisomers 4l with in of 90% regioisomers the (4k yield putative and with5k () 4k inπ high- andallyl93% 5kregioselectivityyield nickel) in. 93The species% yieldratio .[13].of . TheThe 4k :ratioIn 5kbranched thewas of reaction4kdetermined:5k isomer was of determined the(to5l )be γwas -57:43alkyl not to detectedbe 57:43 Grignard1 Grignard reagent reagent with the with putative the putative π-allyl π -allyl nickel nickel species species [13]. [13]. In In the the reaction reaction of of the the γ-alkyl using(entryusing 1H5 ). H NMRThe(using entryNMR regioselectivity spectroscopy 15H spectroscopy). NMRThe regioselectivity spectroscopy (entry in (entrythis 4). reaction The 4).(entry in Thereactionthis probably 4). reaction The of reactiona depends mixtureprobablyof a mixture of of ona depends mixture2j both andof 2jmaximizing 2k ofandon ( 2j both : 2kand = (maximizing2j 2k67:33) the:2k (2j resonance=: 2k gave67:33) = 67:33) the gave resonance gave the the substituted(entry 5).substituted allylicThe regioselectivity ether, allylic the steric ether, ininfluence the this steric reaction should influence probablyoperate should predominantly dependsoperate predominantly on forboth the maximizing formation for the offormation thethea resonance of the stabilizationsubstitutedlinear productstabilization Tableenergy allylic 4l 4. inon Theether, 90%theenergy cross coupling yieldthe -oncoupling steric withthe product coupling influencehigh reaction regioselectivityand product of minimizingshould allylic and ethersoperate minimizing. stericThe 2 withbranched predominantlyhindra aryl stericncemagnesium isomer inhindra the couplingfornce(5l )reagents theinwas the formation ofnot coupling the3 .detected of thethe product.linearstabilization product linearproduct. 4lenergy productin 90% on yield 4l the in with 90%coupling highyield regioselectivity withproduct high andregioselectivity .minimizing The branched. The steric isomer branched hindra (5l) isomerwasnce notin ( 5l thedetected) was coupling not detected of the (Grignardproduct.entry(entry 5). 5 The ). reagentGrignard(entry The regioselectivity regioselectivity5 ). with The reagent theregioselectivity putative within this in the thisreaction π putative -inreactionallyl this probably nickel reaction πprobably-allyl species depends probably nickel depends [13]. on species depends bothIn on the [13].maximizingboth on reaction Inbothmaximizing the maximizing ofthe reaction the resonance theγ- alkyl ofresonancethe the resonance γ-alkyl Grignard reagent with the putative π-allyl nickel species [13]. In the reaction of the γ-alkyl stabilizationsubstitutedstabilizationsubstitutedstabilization allylic energy energy ether, on allylic theonenergy the thecoupling stericether, couplingon theinfluence the product coupling steric product should andinfluence product minimizingand operate minimizing should and minimizingpredominantly steric operate sterichindra predominantly steric hindrance for inhindra the ncethe formation couplinginnce forthe ain the couplingthe offormation coupling thethea of the of ththee substitutedTable allylic 4. The Tableether, cross- 4.coupling the The stericcross reaction-coupling influence of allylic reaction should ethers of allylic 2 operatewith ethers aryl magnesiumpredominantly 2 with aryl magnesiumreagents for 3. thereagents formation 3. of the Grignardproduct.Grignard reagentproduct.Grignard Table reagent 4.with The reagent with thecross the putative with-coupling putative the π putativereaction-allyl π-allyl nickel ofπ -allylic nickelallyl species nickel ethers species [13]. 2 species with [13].In thearyl [13].In magnesium reaction the In reaction the of reaction reagents the ofγ - alkyl the of 3 . a the γ-alkyl γ-alkyl substitutedproduct.substituted substituted allylic allylic ether, ether, allylic the thesteric ether, steric influence the influence steric should influence should operate should operate predominantly operate predominantly predominantly for the for formation the for formationthe offormation the of th ofe the Table 4. The cross-coupling reaction of allylic ethers 2 with arylmagnesium reagents 3. a a Moleculesproduct.product.2019 product. , 24, 2296 Table 4. The cross-coupling reaction of allylic ethers 2 with arylmagnesium reagents 3. 5 of 12 Table 4. The cross-coupling reaction of allylic ethers 2 with arylmagnesium reagents 3. a a a TableTable 4. The 4. TableThe cross cross -4.coupling The-coupling cross reaction-coupling reaction of allylic reaction of allylic ethers of ethersallylic 2 with ethers2 aryl withmagnesium 2 aryl withmagnesium aryl magnesiumreagents reagents 3. reagents 3. a 3. Table 4. The cross-coupling reaction of allylic ethers 2 with arylmagnesium reagents 3. a

b 4b, 94% 4c, 94% 4d, 95%

4b, 94% 4b, 94% 4c, 94% 4c, 94% 4d, 95% b 4d, 95% b

4b, 94% 4c, 94% 4d, 95% b 4b, 94% 4b , 94% 4c, 94% 4c, 94% 4d, 95% b 4d, 95% b

4b, 94% 4c, 94% 4d, 95% b

b b 4b4, 94%b, 94% 4 b, 94% 4c, 94%4c , 94%4c, 94% 4d, 95% 4d4d, ,95% 95% b 4b, 94% 4c, 94% 4d, 95% b 4e, 96% 4f, 85% c 4g, 79% d 4e, 96% 4e, 96% 4f, 85% c 4f, 85% c 4g, 79% d 4g, 79% d

4e, 96% 4f, 85% c 4g, 79% d

4e, 96% 4e, 96% 4f, 85% c 4f, 85% c 4g, 79% d 4g, 79% d 4e, 96% 4f, 85% c 4g, 79% d

c c d d 4e, 96% 4e, 96% 4f, 85% 4f, 85% 4g, 79% 4g, 79% 4h,44 80%ee,, 96%96%e 4f44i,f 85%,, 78%85% c b c 4g, 479%g4j, ,79% 89%d df a e e b b f f The reaction4h, 80% was carried 4eh, out80% using 2 (0.5 mmol)4i, 78% and 3 (0.754i, mmol)78%b in the presence 4 ofj, 1b89%(0.005 4 mmol,j, 89% 1.0f mol%) in 4h, 80% 4i, 78%b c 4j, 89% Et2O (5 mL) for 24 h at room temperature. Isolated yield. 2.5 mol% of 1b was used. 2.5 mol% of 1b and 1.5 mmol a The reactiona The was reaction carried was out using carried 2 out(0.5 usingmmol) 2 and(0.5 3mmol) (0.75 mmol)and 3 (0.75in the dmmol) presence in the of presence1b (0.005 of 1b (0.005 ofa3f were used. The reaction was carried out under reflux conditions for 72 h. 2.5 mol% of 1b and 1.1 mmol of 3g The reaction wase carriede out using 2 (0.5 mmol)b and b3 (0.75e mmol)b in the f presenceb off 1b (0.005 weremmol used., 1.04 hmol% Themmol, 80% reaction) , in 1.0 Et4 h2mol% wasO, 80%(5 carriedmL)) in Etfor2 outO 24 ( under5 h mL) at 4room i refluxfor, 78% 24 temperature. conditions h at4 roomi, 78% fortemperature. Isolated 24 h. 2.5yield. mol%Isolated 42.5j of, 89%mol% 1byield.and of 1.5 4 2.51bj, mmol89% mol%was of of3h 1bwere was f b used.mmol Thec , 1.0 reaction mol% wasc ) in carried Et2O out(5 mL) under for reflux 24 h conditions at room fortemperature. 72 h. 2.5 mol% Isolated of 1b andyield. 1.5 mmol 2.5 mol% of 3a were of 1b used. was used. 2.5 mol%used. of 2.5 1be mol%and 1.5 of mmol1b and of 1.5 3f mmolwere used of 3f. Thewereb reaction used. The was reaction carried was out under carried reflux out funder reflux Moleculesa c20194a, h24, FOR80% PEER REVIEW 4i, 78% 4j, 89% 7 Molecules 2019 used.The, 24 reaction FOR 2.5 PEER The mol% was reactionREVIEW carriedd of 1b was outand carriedusing d1.5 mmol 2 out(0.5 usingmmol)of 3f 2were and(0.5 mmol) 3used (0.75. andmmol) The 3 reaction ( 0.75in the mmol) presence was in carried the of presence1b out(0.005 under of 1b reflux(70.005 Moleculesconditions 2019, 244h FORfor,conditions 80% 72 PEER h. e 4REVIEW2.5h for, 80%mol% 72 h.e of 2.51b mol%and 1.1 4ofi , mmol 1b78% and bof 1.1 3g4i , mmol w78%ere busedof 3g. Thewere reaction used4j., The89% was reaction f carried4j, 89% wasout f carried out7 MoleculesMolecules 20192019,, 2424 FORFOR PEERPEER REVIEWREVIEW2 2 b b 77 Molecules mmol2019a , 24, 1.0 FOR mol%mmol PEER) ,in REVIEW1.0 Et mol%Od (5 )mL) in Et fore O 24 (5 hmL) at room fore 24 temperature. h at room temperature. Isolated yield. Isolated 2.5 mol%yield. of 2.5 1ba mol%was of 1b7 was underconditions The reflux reactionunder conditionsforTable was72 reflux h. 5. carried for The conditions2.5 24 cross-couplingmol% h out. 2.5 forusingof mol% 1b24 hand2 .of ( reaction0.5 2.51b 1.1 mol%andmmol) mmol 1.5 of of mmolvarious and 1bof and3g 3 of ( w 0.751.5 allylic3here mmolw mmol)ereused ethers used of. The3hin. 2 The w thewithreactionere reaction presenceused3aa . . Thewas was ofreaction carried 1b (0.005 wasout c c aused. 2.5 mol%used.a of Table2.5 1b mol%and 5. The1.5 of cross mmol1b and-coupling of 1.5 3f mmolwere reaction usedof 3f. ofwere The various reactionused allylic. The was reactionethers carried 2 with was outa 3 carriedundera. reflux out under reflux The reactionTable The was reaction5. carriedThee cross was out- coupling carriedusing 2e out( 0.5reaction usingfmmol) of2 and (various0.5 fmmol)3b (0.75 allylic mmol)and ethers3 ( 0.75in the 2 mmol) with presence 3 ina. the ofa presence1b (0.005f of 1b (0.005 carriedunder out reflux undercarried conditions reflux oute under conditions2 for reflux 24 forh conditions. 72 2.5 h. mol% 2.5 for mol% 72of h 1bof. 2.51bandb andmol% 1.5 1.5 mmolof mmol 1b and of of 3h1.53a weremmolwere used. a used ofb 3a .were The used.reactionf was mmol, 1.044 mol%hhTable,, 80%80%) d in 5. TheEt O cross (5 dmL)-coupling for 24 reaction h at4 i4room, i78%, of78% various temperature. allylic ethersIsolated 2 with yield. 3a4 aj ., 489%2.5j, 89%mol% of 1b was conditions TableforTableconditions 72 h.5.5. TheThe 2.5 for crosscrossmol% 72 h.--coupling couplingof 2.5 1b mol%and reactionreaction 1.1 of mmol1b andofof variousofvarious 1.1 3g mmol w ere allylicallylic usedof 3g ethersethers. Thewere 2reaction2 used withwithb . 3The3 aawas.. areaction carriedb wasout carried out mmol, 1.0c mol%mmolTable) ,in 5.1.0 EtThe 2mol%O cross(5 mL)) in-coupling Etfor2O 24 (5 h mL) atreaction room for 24 temperature.fof h variousat room allylictemperature. Isolated ethers yield. Isolated2 with 2.5 3mol% ayield.. of 2.5 1b mol%was of 1b was used.carried 2.5out mol%under ofreflux 1b and conditions 1.5e mmol for of72e 3fh. were 2.5 mol% used of. The 1b and reaction 1.5 mmol was of carried 3a were out used. under reflux undera c refluxunder conditions creflux forconditions 24 h. 2.5 for mol% 24 h . of 2.5 1b mol%and 1.5 of mmol 1b and of 1.5 3h mmolwere usedof 3h. Thewere reaction used. The was reaction was used.a The The 2.5 reaction reaction mol%used. of was 2.5 1b mol% carriedand 1.5 of out mmolout1b and usingusing of 1.5 3f 2 2 mmolwere( 0.5(0.5 mmol) usedofmmol) 3f. Thewereand and reaction 3used (30.75 (.0.75 The mmol) was mmol) reaction carried in thein was out the presence under carried presence reflux out of 1bunder of (1b0.005 reflux(0.005 d f f carriedconditions out undercarried for 72reflux out dh. under conditions 2.5 mol%refluxd for conditionsof 72 1b h .and 2.5 for 1.1mol% 72 mmol h of. 2.51b ofmol%and 3g 1.5 wof mmolere 1b andused of 1.53.a Theweremmol reaction bused. of 3a were was used. carried out conditionsmmol, 1.0 forconditions mol% 72 h. ) in2.5 for Et mol% 272O h.(5 ofmL) 2.5 1b mol%forand 24 1.1 ofh mmolat1b room and of 1.1 temperature.3g mmolwere usedof 3g . Isolated Thewere reaction used yield.. The was 2.5reaction carriedb mol% wasout of 1bcarried was out mmol, 1.0 mol%) in Et2O (5 mL) efor 24 h at room temperature. Isolated yield. 2.5 mol% of 1b was under refluxc conditions for 24e h. 2.5 mol%e of 1b and 1.5 mmol of 3h were used. The reaction was underused. reflux c 2.5under conditions mol% reflux of 1bfor conditions and24 h .1.5 2.5 for mmol mol% 24 hof . of 3f2.5 1b were mol%and 1.5used of mmol 1b. Theand of reaction1.53h mmolwere used wasof 3h .carried Thewere reaction used out. underThe was reaction reflux was used. 2.5 mol% of 1b and 1.5 mmol of 3f f were used. The reaction was carried out under reflux carriedcarriedconditions out out undercarried underfor reflux72 out refluxh. under dconditions 2.5 conditions mol%reflux for ofconditions 721b for h and. f72 2.5 1.1forh mol%. 72mmol2.5 h of.mol% f 2.51b of andmol%3g of w1.51b ereof mmoland 1b used and 1.5 of. 1.5Themmol3a weremmol reaction of used. of3a 3 were a was were carriedused. used. out conditions for 72 h. d 2.5 mol% of 1b and 1.1 mmol of 3g were used. The reaction was carried out under reflux conditions for 24 h. e 2.5 mol% of 1b and 1.5 mmol of 3h were used. The reaction was under reflux conditions for 24 h. e 2.5 mol% of 1b and 1.5 mmol of 3h were used. The reaction was carried out under reflux conditions for 72 h. f 2.5 mol% of 1b and 1.5 mmol of 3a were used. f carriedEntry out under reflux conditions2 for 72 h. 2.5 mol% of 1bX and (mol%) 1.5 mmol of4/5 3a were used.4 + 5 (%) Entry 2 X (mol%) 4/5 4 + 5 (%) EntryEntry 2 2 2b’ X (mol%)X (mol%) 4/5 4/5 4 + 45 +(%) 5 (%) EEntryntry 1 22 XX (mol%)(mol%)1.0 44/54/5a:5a = >99:<414 ++ 55 (%)(%)88 Entry 2 2b (2cisb’:trans = 86:14)X (mol%) 4/5 4 + 5 (%) 1 1 0 2b’ 2b’ 1.01.0 4a:4a5a: 5a= >99= >:<99:1 <188 88 1 cis trans 2b’ 1.0 4a:5a = >99:<1 88 11 2 ( : (cis(:transcis= :86:14)trans2b’ = 86 =2: 14)86g : 14) 11.0.0 2.5 44aa::5a5a4 ==k :>99>995k :<=:< 5411 :46 8888 96 1 ((ciscis::transtrans == 8686::14)14) 1.0 4a:5a = >99:<1 88 2 (cis:trans2g = 86:14) 2.5 4k:5k = 54:46 96 2 22 2g 2g 2g 2.52.5 2.5 4k:4k5k4k: :5k=5k 54 ==: 465454:46 :46 96 96 96 22 3 22gg 2h 22.5.5 2.5 44kk::5k5k4a =:=5a 5454 =: :46>9946 :<1 9966 94 3 2h 2.5 4a:5a = >99:<1 94 3 2h 2.5 4a:5a = >99:<1 94 33 3 2h 22hh 2.522.5.5 44aa::4a5a5a: 5a == >99>99= >:<:<99:11 <19944 94 3 4 2h 2i 2.5 2.5 4a:5a4 k=: 5k>99 =:< 571 :43 94 93

4 4 2i 2i 2.5 2.5 4k:5k4k :=5k 57 =: 4357 :43 93 93 44 4 2i 22ii 2.522.5.5 44kk::4k5k5k: 5k== 5757=::434357:43 9933 93 4 2i 2j 2.5 4k:5k = 57:43 93

5 2j 2.5 4l:5l = >99:<1 90 2j 2j 2k 22jj 5 2j (2j:2k = 67:33) 2.5 4l:5l = >99:<1 90 5 5 2k 2.5 2.5 4l:5l4 l=:5l >99 = >99:<1 :<1 90 90 55 5 2k 2k 2.522.5.5 44ll::4l5l5l: 5l== >99>99= >:<:<99:11 <19900 90 (22kj:2k 22=kk 67 :33) a The reaction was carried out using( 2j :(0.52(2kj :–=21.0 k67 = :mmol) 33)67: 33) and 3 (0.75–1.5 mmol) in the presence of 1b (2j:2k((22=jj::267:33)2kk == 6767::33)33) (0.005–0.0125 mmol, 1.0–2.5 mol%) in Et2O (5 mL) for 24 h at room temperature. Isolated yield. (Ar = a Thea reaction was carried out using 2 (0.5–1.0 mmol) and 3 (0.75–1.5 mmol) in the presence of 1b aa The4 reaction-MeOC6H was4). carried out using 2 (0.5–1.0 mmol) and 3 (0.75–1.5 mmol) in the presence of 1b a TheThe reactionreaction waswas carriedcarried outout usingusing 22 (0.5(0.5––1.01.0 mmol)mmol) andand 33 (0.75(0.75––1.51.5 mmol)mmol) inin thethe presencepresence ofof 1b1b (0.005 Thea – reaction0.0125 mmol, was carried1.0–2.5 outmol%) using in Et2 2(0.5O (5– 1.0mL) mmol) for 24 andh at 3room (0.75 temperature.–1.5 mmol) in Isolated the presence yield. (ofAr 1b = (0.005The reaction–0.0125 mmol, was carried 1.0–2.5 out mol%) using 2in(0.5–1.0 Et2O (5 mmol) mL) for and 243 h(0.75–1.5 at room mmol) temperature. in the presence Isolated of yield.1b (0.005–0.0125 (Ar = (0.005(0.005––0.01250.0125Finally, mmol,mmol, we investigated1.01.0––2.52.5 mol%)mol%) the inin EtreactivityEt22OO (5(5 mL)mL) of forfor the 2424 allylic hh atat roomroom C(sp 3temperature.temperature.)–O and nap IsolatedhIsolatedthyl C( yield.yield.sp2)–O ((ArAr bond == s in 2l 4(0.005-MeOCmmol,–0.01256H 1.0–2.54). mmol, mol%) 1.0 in–2.5 Et2 Omol%) (5 mL) in for Et 242O h(5 at mL) room for temperature. 24 h at room Isolated temperature. yield. (Ar Isolated= 4-MeOC yield.6H 4().Ar = 4-MeOC6H4). 44--MeOCMeOC66HH44).). 3 4-MeOC(Scheme6H4 ). 2). Scission of the allylic C(sp )–O bond in 2l selectively occurred and thus, allylated 3 2 Finally, we investigated the reactivity of the allylic C(sp )–O3 and naphthyl C(sp )–O2 bonds in 2l Finally,product we4a was investigated obtained inthe 68% reactivity yield. of the allylic C(33sp )–O and naphthyl C(22sp )–O bonds in 2l Finally,Finally, wewe investigatedinvestigated thethe reactivityreactivity3 ofof thethe allylicallylic C(C(spsp 3))––OO andand napnaphhtthhylyl C(C(spsp 2))––OO bondbondss inin 2l2l (SchemeFinally, 2). Scissionwe investigated of the allylicthe reactivity C(sp )– ofO3 the bond allylic in 2lC( spselectively)–O and occurrednaphthyl C( andsp thus,)–O bond allylateds in 2l (Scheme(Scheme 2). 2).Scission Scission of ofthe theallylic allylic C( sp C(33sp)–O) – bondO bond in in2l selectively2l selectively occurred occurred and and thus, thus, allylated allylated product(Scheme(Scheme 4a 2). 2). was ScissionScission obtained of of in the the 68% allylicallylic yield. C( C( sp sp3))––OO bond bond inin 2l2l selectivelyselectively occurredoccurred and and thus, thus, allylated allylated productproduct 4a was4a was obtained obtained in 68%in 68% yield. yield. productproduct 4a4a waswas obtainedobtained inin 68%68% yield.yield.

Scheme 2. Selective cleavage of the allylic C(sp3)–O bond in cinnamyl naphthyl ether 2l catalyzed by 1b.

3 Scheme 2. Selective cleavage of the allylic C(sp )–O3 bond in cinnamyl naphthyl ether 2l catalyzed by SchemeScheme 2. Selective 2. Selective cleavage cleavage of the of theally allylic C(licsp C(33)sp–O) –bondO bond in cinnamyl in cinnamyl nap naphthhylt hetheryl ether 2l catalyzed 2l catalyzed by by 1bSchemeScheme. 2.2. SelectiveSelective cleavagecleavage ofof thethe allyallyllicic C(C(spsp3))––OO bondbond inin cinnamylcinnamyl napnaphhtthhylyl etherether 2l2l catalyzedcatalyzed byby 1b. 1b. 1b1b.. Molecules 2019, 24 FOR PEER REVIEW 7

Table 5. The cross-coupling reaction of various allylic ethers 2 with 3a. a

Entry 2 X (mol%) 4/5 4 + 5 (%) 2b’ 1 1.0 4a:5a = >99:<1 88 (cis:trans = 86:14)

2 2g 2.5 4k:5k = 54:46 96

3 2h 2.5 4a:5a = >99:<1 94

4 2i 2.5 4k:5k = 57:43 93

2j

5 2.5 4l:5l = >99:<1 90 2k (2j:2k = 67:33)

Moleculesa The2019 reaction, 24, 2296 was carried out using 2 (0.5–1.0 mmol) and 3 (0.75–1.5 mmol) in the presence of 1b6 of 12 (0.005–0.0125 mmol, 1.0–2.5 mol%) in Et2O (5 mL) for 24 h at room temperature. Isolated yield. (Ar = 4-MeOC6H4). Finally, we investigated the reactivity of the allylic C(sp3)–O and naphthyl C(sp2)–O bonds in 2l Finally, we investigated the reactivity of the allylic C(sp3)–O and naphthyl C(sp2)–O bonds in 2l (Scheme2). Scission of the allylic C(sp 3)–O bond in 2l selectively occurred and thus, allylated product (Scheme 2). Scission of the allylic C(sp3)–O bond in 2l selectively occurred and thus, allylated 4a was obtained in 68% yield. product 4a was obtained in 68% yield.

MoleculesScheme 2019, 24 2. FORSelective PEER REVIEW cleavage of the allylic C(sp3)–O bond in cinnamyl naphthyl ether 2l catalyzed 8 Scheme 2. Selective cleavage of the allylic C(sp3)–O bond in cinnamyl naphthyl ether 2l catalyzed by by 1b. 2.3. Reaction1b. Mechanism 2.3. Reaction Mechanism We examined the stoichiometric reaction to gain insight into the reaction mechanism (Table 6).

In theWe reaction examined of thenickel stoichiometric(II) complex reaction 1b with to an gain equimolar insight into amount the reaction of allylic mechanism ether 2b (Table, oxidative6). In additionthe reaction of the of nickel(II) C-O bond complex of 2b to1b 1bwith did annot equimolar occur and amount 2b was of recovered allylic ether in2b 96%, oxidative. In contrast, addition when of 1bthe was C-O bondtreated of 2b withto 1ban didexcess not occuramount and of2b phenylwas recoveredmagnesium in 96%. reagent In contrast, 3b, 1b whenwas converted1b was treated into anotherwith an excess nickel amount species of. In phenylmagnesium the 31P{1H} NMR reagent spectrum3b, 1b, thewas signal converted derived into another from 1b nickel (37.5 species. ppm) disappearedIn the 31P{1H} [26 NMR] and spectrum, a new signal the signalwas observed derived fromat 49.11b ppm(37.5, whoseppm) disappeared resonance was [26 ]due and to a new the formationsignal was ofobserved a new at nickel 49.1 ppm, species whose. However, resonance characterization was due to the formationof this nickel of a new complex nickel was species. not successful.However, characterization Subsequently, we of thisexamined nickel complexthe reaction was with notsuccessful. various amount Subsequently,s of 3a in we the examined presencethe of 1breaction and 2b with. The various obtained amounts results of are3a insummarized the presence in of Table1b and 6. In2b the. The reaction obtained using results a mixture are summarized of 1b and 2bin Tablewith 61. equivalent In the reaction of 3a using, the coupl a mixtureed product of 1b and 4a was2b with not detected 1 equivalent with of 2b3a being, the coupled recovered product in 83%4a. Inwas the not case detected of the with reaction2b being using recovered 2 equivalents in 83%. of In3a the, the case coupled of the reactionproduct using(4a) was 2 equivalents formed in of23%3a, yield.the coupled Using product3 equivalents (4a) was of 3a formed, the reaction in 23% yield.proceed Usinged smoothly 3 equivalents and 2b of was3a, thecompletely reaction consumed proceeded tosmoothly give the and coupled2b was product completely (4a) in consumed 83% yield to, along give thewith coupled the formation product of (4a 4,)4′ in-b 83%itolyl yield, (6a, 0.19 along mmol with). Thethe formation reaction using of 4,4 40-bitolyl equivalents (6a, 0.19 of 3a mmol). also gave The reactionthe product using (4a 4 equivalents) in 83% yield. of 3a Therefore,also gave thewe assumedproduct ( 4athat) in two 83% or yield. more Therefore,equivalents we of assumed the arylmagnesium that two or morereagent equivalents are required of the to arylmagnesiumfor the reaction toreagent proceed are via required the generation to for the reaction of an anionic to proceed nickel( via0) the species, generation which of is an the anionic active nickel(0) species species, for the activationwhich is the of activethe allylic species ether for (vide the activation infra). of the allylic ether (vide infra).

a Table 6. The stoichiometric reaction of allylicallylic ether 2b with aryl Grignard reagentreagent 3a3a.. a

EntryEntry XX (equiv)(equiv) 4a (%)4a (%)b b 6a (mmol)6a c (mmol)Recoveryc Recoveryof 2b (%) of b 2b (%) b 11 11 N.D. N.D. 0.03 0.0383 83 2 2 23 0.09 40 32 32 23 830.09 0.1940 0 43 43 83 830.19 0.230 0 a Reaction conditions:4 1b (0.24 mmol), 2b (0.2 mmol),83 and 3a in Et0.232O (5 mL) at room temperature0 (Ar = 4-MeOC6H4). b The yield of 4a and recovery of 2b were determined by 1H NMR analysis using pyrazine as the internal standard. ac ReactionThe amount conditions: of 6a was determined1b (0.2 mmol), by 1H 2b NMR (0.2 analysis mmol), using and 3a pyrazine in Et2O as (5 the mL) internal at room standard. temperature (Ar = 4-MeOC6H4). b The yield of 4a and recovery of 2b were determined by 1H NMR analysis using pyrazine as the internal standard. c The amount of 6a was determined by 1H NMR analysis using pyrazine as the internal standard. Although the detailed reaction mechanism for the nickel catalyzed allyl-aryl coupling reaction was not clear, a plausible mechanism is proposed in Scheme 3 [13,28]. Initially, nickel(II) complex 1b is converted into anionic nickel(0) species I through its reaction with at least 2 equivalents of arylmagnesium reagent accompanied by the formation of a biaryl. Then, the low valent nickel(0) species (I) reacts with the allylic electrophile at the nickel center to afford π-allyl nickel species II (as shown in Table 5): For example, γ-alkyl substituted allylic ether 2g was converted into a mixture of linear and branched isomers. We have recently reported that the steric and electronic properties of the nickel(II) complexes 1 [26,27]. The DFT calculations of complexes 1 reveal that the highest occupied molecular orbital (HOMO) levels of these complexes increase in the order 1a  1b < 1c  1d. We expected that complexes 1c and 1d worked as effective catalysts for this coupling reaction. However, the bulky substituent (mesityl group) on the ligand framework inhibits to form π-allyl nickel species derived from 1c and 1d. Therefore, complexes 1c and 1d show poor catalytic activities. In contrast, complex 1b acts as an effective catalyst for the coupling reaction, because of constructing an appropriate steric and electronic environment around nickel center by the O,N,P-pincer ligand. After the formation of π-allyl nickel species II, its subsequent transmetalation

Molecules 2019, 24, 2296 7 of 12

Although the detailed reaction mechanism for the nickel catalyzed allyl-aryl coupling reaction was not clear, a plausible mechanism is proposed in Scheme3[ 13,28]. Initially, nickel(II) complex 1b is converted into anionic nickel(0) species I through its reaction with at least 2 equivalents of arylmagnesium reagent accompanied by the formation of a biaryl. Then, the low valent nickel(0) species (I) reacts with the allylic electrophile at the nickel center to afford π-allyl nickel species II (as shown in Table5): For example, γ-alkyl substituted allylic ether 2g was converted into a mixture of linear and branched isomers. We have recently reported that the steric and electronic properties of the nickel(II) complexes 1 [26,27]. The DFT calculations of complexes 1 reveal that the highest occupied molecular orbital (HOMO) levels of these complexes increase in the order 1a 1b < 1c ≈ ≈ 1d. We expected that complexes 1c and 1d worked as effective catalysts for this coupling reaction. However, the bulky substituent (mesityl group) on the ligand framework inhibits to form π-allyl nickel species derived from 1c and 1d. Therefore, complexes 1c and 1d show poor catalytic activities. In contrast, complex 1b acts as an effective catalyst for the coupling reaction, because of constructing anMolecules appropriate 2019, 24 FOR steric PEER and REVIEW electronic environment around nickel center by the O,N,P-pincer ligand.9 After the formation of π-allyl nickel species II, its subsequent transmetalation with the arylmagnesium with the arylmagnesium reagent leads to the formation of a σ-allyl nickel species bearing aryl ligand reagent leads to the formation of a σ-allyl nickel species bearing aryl ligand III and/or IV. We assumed III and/or IV. We assumed that the formation of intermediate III is more favorable than IV due to that the formation of intermediate III is more favorable than IV due to steric hindrance. Therefore, steric hindrance. Therefore, the selectivity in the reaction was influenced by the substituent on the the selectivity in the reaction was influenced by the substituent on the allylic substrate. Finally, the allylic substrate. Finally, the desired products 4 and/or 5 are released via reductive elimination from desired products 4 and/or 5 are released via reductive elimination from the Ni center to regenerate the the Ni center to regenerate the nickel(0) species (I) and thus, the catalytic cycle is completed. One of nickel(0) species (I) and thus, the catalytic cycle is completed. One of the possible reaction pathways the possible reaction pathways involved in an allylic substitution reaction is the attack of the involved in an allylic substitution reaction is the attack of the nucleophile on π-allyl nickel species I; nucleophile on π-allyl nickel species I; this mechanism cannot be excluded. this mechanism cannot be excluded.

Scheme 3. A plausible catalytic cycle for the cross-coupling reaction of an allylic ether and arylmagnesium reagent. Scheme 3. A plausible catalytic cycle for the cross-coupling reaction of an allylic ether and 3. Materialsarylmagnesium and Methods reagent.

3.1.3. Materials General Information and Methods All manipulations involving air- and moisture-sensitive organometallic compounds were carried 3.1. General Information out under a nitrogen atmosphere, which was dried with SICAPENT (Merck Co., Inc., Germany, Darmstadt),All manipulations using standard involving Schlenk air tube- and or highmoisture vacuum-sensitive techniques. organometallic All solvents compounds were distilled were carried out under a nitrogen atmosphere, which was dried with SICAPENT (Merck Co., Inc., Germany, Darmstadt), using standard Schlenk tube or high vacuum techniques. All solvents were distilled over appropriate drying agents prior to use. Nickel complexes 1a–c [26] and 1d [27] were prepared according to literature methods. Allylic aryl ethers 2a–c, 2e–g, and 2l were prepared from the reaction of their corresponding allylic halides and 4-substituted phenols using K2CO3 in acetone. Allylic methyl ether 2d was prepared via the reduction of the corresponding aldehyde using NaBH4 followed by methylation using methyl iodide. Allylic methyl ethers 2h and 2i were prepared from addition of the corresponding aldehyde with vinylmagnesium bromide followed by methylation using methyl iodide. A mixture of 2j and 2k was prepared via the reduction of cinnamyl methyl ketone using NaBH4 followed by a Mitsunobu reaction using 4-methoxyphenol. All other reagents employed in this research were commercially available and used without any further purification. Proton nuclear magnetic resonance (1H NMR), carbon nuclear magnetic resonance (13C{1H} NMR), and phosphorus nuclear magnetic resonance (31P{1H} NMR) spectra were recorded on BRUKER DRX-500 and JEOL ECA 500 spectrometers at ambient temperature. 1H NMR chemical shifts were recorded in ppm using tetramethylsilane (TMS) or the solvent resonance peak as an internal standard (TMS: 0.00 ppm, C6D6: 7.16 ppm). 13C{1H} NMR chemical shifts were recorded in

Molecules 2019, 24, 2296 8 of 12 over appropriate drying agents prior to use. Nickel complexes 1a–c [26] and 1d [27] were prepared according to literature methods. Allylic aryl ethers 2a–c, 2e–g, and 2l were prepared from the reaction of their corresponding allylic halides and 4-substituted phenols using K2CO3 in acetone. Allylic methyl ether 2d was prepared via the reduction of the corresponding aldehyde using NaBH4 followed by methylation using methyl iodide. Allylic methyl ethers 2h and 2i were prepared from addition of the corresponding aldehyde with vinylmagnesium bromide followed by methylation using methyl iodide. A mixture of 2j and 2k was prepared via the reduction of cinnamyl methyl ketone using NaBH4 followed by a Mitsunobu reaction using 4-methoxyphenol. All other reagents employed in this research were commercially available and used without any further purification. Proton nuclear magnetic resonance (1H NMR), carbon nuclear magnetic resonance (13C{1H} NMR), and phosphorus nuclear magnetic resonance (31P{1H} NMR) spectra were recorded on BRUKER DRX-500 and JEOL ECA 500 spectrometers at ambient temperature. 1H NMR chemical shifts were recorded in ppm using tetramethylsilane (TMS) or the solvent resonance peak as an internal standard 13 1 (TMS: 0.00 ppm, C6D6: 7.16 ppm). C{ H} NMR chemical shifts were recorded in ppm using the 31 1 solvent resonance peak as an internal standard (CDCl3: 77.0 ppm, C6D6: 128.0 pm). P{ H} NMR chemical shifts were recorded in ppm using H3PO4 as an external standard (H3PO4: 0.0 ppm).

3.2. General Procedure for the Cross-Coupling Reaction of Allylic Ethers with Arylmagnesium Reagents A 50 mL Schlenk tube was charged with 1b (1.0–2.5 mol%), the respective allylic electrophile (1.0 mmol), Et2O (2.5–5 mL, 0.2 M based on the electrophile), and the aryl Grignard reagent (1.5–3.0 equiv.) at room temperature. The coupling reaction was carried out at room temperature for 24 h. After quenching with 1 M HCl aq. (5 mL), the aqueous layer was extracted with EtOAc (5 3 mL). × The combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSO4. After filtration and removal of all volatiles from the filtrate, the residue was purified by column chromatography on silica gel. 1-Cinnamyl-4-methylbenzene (4a): The compound 4a was synthesized from 1-methoxy-4-{[(2E)-3- phenylprop-2-en-1-yl]oxy}benzene 2b (240.9 mg, 1.00 mmol) with p-tolylmagnesium bromide 3a (1.4 mL, 1.1 M in THF, 1.5 mmol) in the presence of 1b (4.1 mg, 1 mol%) in Et2O (5 mL) at room temperature for 24 h (198.0 mg, 95% yield, colorless liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [29].

The compound 4a was synthesized from 2b0 (cis:trans = 86:14, 119.6 mg, 0.50 mmol) with 3a (0.70 mL, 1.1 M in THF, 0.77 mmol) in the presence of 1b (2.0 mg, 1 mol%) in Et2O (2.5 mL) at room temperature for 24 h (91.1 mg, 88% yield). The compound 4a was synthesized from (1-methoxy-2-propen-1-yl)benzene 2h (147.3 mg, 0.99 mmol) with 3a (1.40 mL, 1.1 M in THF, 1.5 mmol) in the presence of 1b (10.1 mg, 2.5 mol%) in Et2O (5 mL) at room temperature for 24 h (194.2 mg, 94% yield). The compound 4a was synthesized from 2-{[(2E)-3-phenylprop-2-en-1-yl]oxy}naphthalene 2l (260.9 mg, 1.00 mmol) with 3a (1.4 mL, 1.09 M in THF, 1.5 mmol) in the presence of 1b (10.1 mg, 2.5 mol%) in Et2O (5 mL) at room temperature for 24 h. The yield of 4a was determined by 1H NMR analysis of the crude product using pyrazine as the internal standard (68% yield). (E)-Prop-1-ene-1,3-diyldibenzene (4b). The compound 4b was synthesized from 2b (238.8 mg, 0.99 mmol) with phenylmagnesium bromide 3b (1.4 mL, 1.1 M in THF, 1.5 mmol) in the presence of 1b (4.06 mg, 1 1 mol%) in Et2O (5 mL) at room temperature for 24 h (181.2 mg, 94% yield, colorless liquid). H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [30]. Molecules 2019, 24, 2296 9 of 12

1-Cinnamyl-4-methoxylbenzene (4c). The compound 4c was synthesized from 2b (238.4 mg, 0.99 mmol) with 4-methoxylphenylmagnesium bromide 3c (3.0 mL, 0.5 M in THF, 1.5 mmol) in the presence of 1b (3.90 mg, 1 mol%) in Et2O (5 mL) at room temperature for 24 h (209.1 mg, 94% yield, colorless liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [29]. 1-Cinnamyl-N,N-dimethylaniline (4d). The compound 4d was synthesized from 2b (239.2 mg, 1.00 mmol) with 4-N,N-dimethylaminophenylmagnesium bromide 3d (2.0 mL, 0.75 M in THF, 1.5 mmol) in the presence of 1b (10.2 mg, 2.5 mol%) in Et2O (5 mL) at room temperature for 24 h (224.5 mg, 95% yield, yellow liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [29]. 1-Cinnamyl-4-fluorobenzene (4e). The compound 4e was synthesized from 2b (241.1 mg, 1.00 mmol) with 4-fluorophenylmagnesium bromide 3e (1.5 mL, 1.0 M in THF, 1.5 mmol) in the presence of 1b (9.9 mg, 2.5 mol%) in Et2O (5 mL) at room temperature for 24 h (230.1 mg, 96% yield, colorless liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [29]. 1-Cinnamylnaphthalene (4f). The compound 4f was synthesized from 2b (122.0 mg, 0.51 mmol) with 1-napthylmagnesium bromide 3f (5.8 mL, 0.26 M in THF, 1.51 mmol) in the presence of 1b (5.1 mg, 1 13 1 2.5 mol%) in Et2O (5 mL) at reflux conditions for 72 h (105.5 mg, 85% yield, white solid). H and C{ H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [31]. 1-Cinnamyl-2-methylbenzene (4g). The compound 4g was synthesized from 2b (240.3 mg, 1.00 mmol) with o-tolyl magnesium bromide 3g (3.5 mL, 0.63 M in THF, 2.2 mmol) in the presence of 1b (10.3 mg, 1 2.5 mol%) in Et2O (5 mL) at reflux conditions for 24 h (164.7 mg, 79% yield, colorless liquid). H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [29]. 1-Cinnamyl-2,4,6-trimethylbenzene (4h). The compound 4h was synthesized from 2b (241.7 mg, 1.01 mmol) with 2,4,6-trimethylphenyl magnesium bromide 3h (3.5 mL, 0.86 M in THF, 3.0 mmol) in the presence of 1b (10.4 mg, 2.5 mol%) in Et2O (5 mL) at reflux conditions for 72 h (191.5 mg, 80% yield, colorless liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [32]. 1-Methoxy-4-[(1E)-3-(4-methylphenyl)prop-1-ene-1-yl]benzene (4i). The compound 4i was synthesized from 1-methoxy-4-{[(1E)-3-(4-methoxyphenoxy)prop-1-en-1-yl]oxy}benzene 2e (134.3 mg, 0.50 mmol) with 3a (0.70 mL, 1.1 M in THF, 0.77 mmol) in the presence of 1b (5.0 mg, 2.5 mol%) in Et2O (2.5 mL) at room temperature for 24 h (92.9 mg, 78% yield, colorless liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [28]. 1-Fluoro-4-[(1E)-3-(4-methylphenyl)prop-1-ene-1-yl]benzene (4j). The compound 4j was synthesized from 1-fluoro-4-{[(1E)-3-(4-methoxyphenoxy)prop-1-en-1-yl]oxy}benzene 2f (131.2 mg, 0.51 mmol) with 3a (1.4 mL, 1.1 M in THF, 1.5 mmol) in the presence of 1b (5.3 mg, 2.5 mol%) in Et2O (2.5 mL) at room temperature for 24 h (102.4 mg, 89% yield, colorless liquid). 1H and 13C{1H} NMR spectra have been attached in the Supplementary Materials. The product was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [33]. Mixture of 1-methyl-4-[(2E)-5-phenylpent-2-ene-1-yl]benzene (4k) and 1-methyl-4-(5-phenylpent-1 -ene-3-yl)benzene(5k). The compounds 4k and 5k were synthesized from 1-methoxy-4-{[(2E)-5- phenylpent-2-en-1-yl]oxy}benzene 2g (130.2 mg, 0.49 mmol) with 3a (0.70 mL, 1.1 M in THF, 0.77 mmol) Molecules 2019, 24, 2296 10 of 12

in the presence of 1b (5.1 mg, 2.5 mol%) in Et2O (2.5 mL) at room temperature for 24 h (110.1 mg, 96% yield, 4k:5k = 54:46, colorless liquid). 1H and 13C{1H} NMR spectra of the mixture of 4k and 5k have 1 been attached in the Supplementary Materials. 4k: H NMR (500 MHz, CDCl3) δ 2.32–2.36 (m, 5H), 2.67–2.71 (m, 2H), 3.22–3.28 (m, 2H), 5.50–5.60 (2H), 7.01–7.03 (m, 2H), 7.07–7.20 (m, 5H), 7.25–7.29 13 1 (m, 2H); C{ H} NMR (125 MHz, CDCl3) δ 21.0, 34.3, 35.9, 38.6, 125.7, 128.2, 128.3, 128.5, 129.0, 129.8, 130.7, 135.3, 137.8, 140.2, 142.0. The product 5k was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [34]. The compounds 4k and 5k were synthesized from (3-methoxypent-4-en-1-yl)benzene 2i (174.9 mg, 0.99 mmol) with 3a (1.4 mL, 1.1 M in THF, 1.5 mmol) in the presence of 1b (10.1 mg, 2.5 mol%) in Et2O (5 mL) at room temperature for 24 h (218.2 mg, 93% yield, 4k:5k = 57:43). 1-Methyl-4-[(3E)-4-phenylbut-3-ene-2-yl]benzene (4l). The compound 4l was synthesized from the mixture of 1-methoxy-4-{[(3E)-4-phenylbut-3-en-2-yl]oxy}benzene 2j and 1-methoxy-4-{[(2E)-1- phenylbut-2-en-1-yl]oxy}benzene 2k (254.7 mg, 2j:2k = 67:33, 1.00 mmol) with 3a (1.4 mL, 1.1 M in THF, 1.5 mmol) in the presence of 1b (10.1 mg, 2.5 mol%) in Et2O (5 mL) at room temperature for 24 h (200.2 mg, 90% yield, colorless liquid). 1H and 13C{1H} NMR spectra of the mixture of 4l and 5l have been attached in the Supplementary Materials. The product 4l was characterized by comparison with the previously reported 1H and 13C{1H} NMR data [29].

4. Conclusions We have described the cross-coupling reaction of allylic aryl ethers with arylmagnesium reagents catalyzed by nickel(II) pincer complexes 1. Complex 1b bearing a β-aminoketonato unit tethering a diphenylphosphino group showed excellent catalyst performance. The reactions of a range of cinnamyl ether derivatives proceeded with high regioselectively to afford solely the linear coupled products in high yield. The coupling reactions of α- and γ-alkyl substituted allylic ethers gave a mixture of linear and branched products. These results indicate that the reaction proceeds via a π-allyl nickel intermediate. Based on stoichiometric reactions, we assumed that an anionic Ni(0) species derived from the reduction of nickel(II) complex 1b with an excess amount of a Grignard reagent was the active intermediate in the reaction. Further investigations on mechanistic aspects and the coupling reactions of various organometallic reagents with organic electrophiles are currently underway in our laboratory.

Supplementary Materials: Supplementary materials including 1H and 13C{1H} NMR spectra are available online. Author Contributions: T.H. and Y.Y. conceived and designed the experiments; K.F., A.O., and E.A. performed the experiments; T.H. and Y.Y. prepared the manuscript; all authors discussed and commented on the manuscript. Funding: This work was supported by JSPS KAKENHI, Grant Numbers 17K05805. This work was also supported by the Collaborative Research Program of the Institute for Chemical Research, Kyoto University, Grant Number 2018-24). Acknowledgments: We thank Hokko Chemical Industry Co., Ltd. for generous support in supplying 4-fuluorophenylmagnesium bromide. Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available from the authors.

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