University of Groningen

Copper catalyzed asymmetric addition of Grignard reagents to ketones and ketiminesRong, Jiawei

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5 Chapter5MechanisticStudiesbyRapidInjectionNMRTechniqueInordertogetmechanisticinsightintoCu(I)-catalyzedasymmetric1,4-and1,2-additionreactionsofGrignardreagentstoenones,effortswerespentontheobservationoftransmetallatedcopperspeciesandshort-livedreactionintermediates(p-andσ-complexes)bymeansoftherapidinjectionNMRtechnique.1H,31PHMBCexperimentsprovideddirectevidenceforthestructureofthespeciesformed upon transmetallation of a copper complex derived from Cu(I) salt/Josiphos ligandwithGrignard reagent (MeMgBr).Unfortunately,noexperimental evidencewas found to support theformationofp-andσ-complexesfromcarbonylsubstratesandtransmetallatedcopperspecies.

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5.1 Introduction5.1.1 Abendinthereactivity:1,4vs1,2As mentioned in the beginning of this thesis, the discovery of Cu(I)-catalyzed asymmetric 1,2-addition of Grignard reagents to ketones was rather unexpected.1 Historically, Cu(I) salts andorganocopper reagents were introduced to promote 1,4-addition and to outcompete theundesired background 1,2-addition of hard organometallic reagents, such as organolithium,Grignard and organozinc reagents.2,3 The introduction of Cu(I)/chiral ferrocenyl phosphinecatalysts by Feringa brought the asymmetric 1,4-addition reaction of Grignard reagents to asynthetically useful level, with a broad scope of substrates and Grignard reagents, as well asexcellent regio- and enantioselectivity.2 Although in all documented 1,4-addition reactionswithenonesassubstratesacertainfractionof1,2-additionproductisalsoformed,typicallywitha5%to20%yield,thisproductwasalwaysfoundtoberacemic.Thegeneralviewwasthatthiswastheresult of non-catalyzed direct addition ofGrignard reagents.2Inspired by intriguing results on adifferent type of reaction, namely Cu(I)-catalyzed C-H bond formation,4 the origin of the 1,2-additionproductwasrevisited.AreportbyLipshutzandco-workersdemonstratedthat inCu(I)-catalyzed asymmetric reduction of α,β-unsaturated ketones the traditional preference for 1,4-selectivity could be shifted to 1,2-addition instead.4 The groups of Harutyunyan andMinnaardstartedbycarryingoutadditionofGrignardreagentstoα-H-substitutedα,β-unsaturatedketoneinthesameconditions(-78oC,inTBME)aspreviouslyreportedbytheFeringagroup.2Tworeactionswerecarriedout,onewithoutanycatalyst(noCu(I)saltorchiralligand)andoneinthepresenceof5mol%ofCu(I)salt,butnochiralligand.5ThepresenceofCu(I)saltwasfoundtoincreasetheamountsofboth the1,2-and1,4-additionproducts.Although the1,4-additionproductwasstillprevalent,theincreasedyieldofthe1,2-additionproductwasaclearsignthatCu(I)saltactsasacatalyst for its formation. Further ligand screening and optimisation of the reaction conditionsallowed significant improvements in both the 1,2-selectivity as well as the enantioselectivity(above90%ofregio-andenantioselectivity),thusprovingthattheoverwhelming1,4-selectivityofCu(I)basedchiralcatalystsintheadditionofGrignardreagentstoα,β-unsaturatedketonescanbeshiftedtowardsthe1,2-additionproduct.5Following this initial discovery of the ability of Cu(I)/chiral ferrocenyl phosphine complex tocatalyze 1,2-addition, the methodology was successfully applied to aryl alkyl ketones,6 diarylketones,7acylsilanes8aswellastosilylimines.TogainmoreinsightintothepreciseroleofCu(I)salts in these transformations,understanding the reactionmechanism is crucial.However, eventhoughCu(I)-catalyzed1,4-additionhasbeendevelopedformorethanthirtyyears,itsmechanismisstillnotfullyelucidated.5.1.2 Themechanismof1,4-and1,2-additionsofstoichiometricamountsof

organocopperreagentstoα,β-unsaturatedcarbonylcompoundsResearch has shown that 1,4-addition of stoichiometric organocopper reagents proceeds via aCu(I)/Cu(III)redoxmechanism(Scheme1a).9,10,11Thismeansanucleophilicattackofthed-orbitalof the Cu(I) atom on an electrophile to reversibly generate a Cu(III) intermediate 2 (oxidativeaddition), followed by decomposition (reductive elimination) to the product and neutral Cu(I)species.Boththeoreticalcalculations10andexperimentaldata11supportthismechanism.Thekeyintermediates, such as cuprate-olefin complex (π-complex) 1 and Cu(III) species 2, have beenobserved separately by NMR experiments, which serves as solid evidence in favor of thismechanism.11On the contrary, nothing is knownabout 1,2-additionof stoichiometric organocopper reagents.Thistransformationislessstudiedsinceitisnotacommonapplicationoforganocopperreagents.Achiralπ-complex1’oforganocopperreagent(Me2CuLi)andcarbonylcompoundshaveonlybeen

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observedrecentlybyThegroupofOgleandBertz(Scheme1b),12simultaneouslywithourreportontheenantioselectivecoppercatalyzedalkylationofarylalkylketones.6In2013,thesamegroupevenmanagedtoisolatethecrystalsoftheπ-complexoffluorenoneandGilmanreagent(Scheme2).12aBecausetheCu(III)intermediate2’hasnotbeendetectedexperimentallyyet,onecanonlymake analogies: based on the previous mechanistic studies on organocopper reagents in 1,4-additions, it is reasonable to assume that the 1,2-addition pathway could either follow ananalogousCu(I)/Cu(III)redoxmechanismtogivespecies2’oradirectnucleophilicadditionafterformingtheπ-complexintermediate1’.

Scheme1.Mechanismof1,4-9,10,11and1,2-additionofstoichiometricamountoforganocuprate

Scheme2.π-ComplexformedbetweenGilmanreagentandcarbonylcompounds(observedbyOgleandco-workersusingRI-NMRandX-raycrystallography).12

5.1.3 Observingtheπ-complexandCu(III)specieswithrapidinjectionNMRCompared to traditional (low temperature) NMR measurements, a rapid injection NMRexperiment provides unique advantages to study fast reactions at very low temperature.11,12Without significantly warming up the system, the substrate can be injected into a solution ofreactants in the NMR tube at low temperature (e.g. -100 oC) during the measurement. Thecontinuous,insitu1DNMRmeasurements(upto1001HNMRcanbecollectedduringthefirstfewminutes) can reveal the whole reaction process: substrates gradually transforming intointermediates and then converting into products. If these intermediates are stable enough,various 1D and 2D NMR experiments can be performed for their identification andcharacterization.Sofar, rapid injectionNMRexperimentshavebeenextremelysuccessful inthemechanistic study of organocopper reactions and many unstable intermediates with shortlifetimes,suchasπ-complexesandCu(III)species,havebeendetectedwiththistechnique.11,12

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Forexample,asshowninScheme3,injectionofcyclohexenoneintoasolutionofMe2CuLi·LiIat-100 oC in THF, led to a clean solutionofπ-complex3 and3.LiI.11aA similarπ-complexwas firstreported by Bertz and co-workers in 1989.13 Coordination of a copper atomwith the π-systeminduces large upfield shifts for the resonances of the C-C double bond: Hα and Hβ (two vinylprotonsofcyclohexenone)shiftedfrom5.90and7.08ppmto3.68and3.19ppm,respectively;CαandCβ (twovinyl carbonsof cyclohexenone) shifted from130.12and151.65ppmto75.82and61.50 ppm. Both methyl groups attached to the copper shifted downfield and split into twodifferentsignals:MeαwasclosertotheHαwhileMeβwaspointingtowardsHβ.Thisconfigurationhasbeenprovenby2DNMRexperiments:NOEsignalsweredetectedbetweenHαandMeαaswellasHβandMeβ.Thecoordinationoflithiumsaltsonlycausedsmalldownfieldshiftsofthecarbonylresonances.11aThesubsequentCu(III)intermediates4couldonlybeobservedafteradditionofTMSCNtotheπ-complexsolution.11aInthepreviousliterature,severalCu(III)specieshavebeenreported,butonlyafewoftheminvolveCu-Cbonds.14Mostofthemaresquareplanar,withtetra-coordination.TheCu(III)species4showedtwomethylsignals:Mecis25.31and0.53ppmfor13CNMRand1HNMR;Metrans 12.43 and 0.05 ppm, respectively. The structure of 4 was indicated by a 13C labelexperiment: introducing13Clabelled13CH3LiandCu13CNtomeasure13C-13Ccouplingconstants2Jacrossacopperatom.11aTheCβiscoupledtoMetranswith2J=38.1HZ,andthecyanoiscoupledtoMeciswith2J=35.4HZ;thecyanoiscoupledtoMetranswith2J=5.4HZandCβiscoupledtoMeciswith 2J =2.9 Hz. This trans-cis pattern is consistent with a square planar pattern.15 The othercharacteristic shiftsare: thecarbonylcarbonofcyclohexenoneshifted to144.73ppm, theCβ to39.68ppmandHβto2.74ppm.Intermediate4isfinallytransformedintothe1,4-additionproduct5afterwarmingupthereactionmixture.

Scheme3.Characteristic1Hand13Csignals/ppmfortheπ-complexandCu(III)species(observed

withtherapidinjectionNMRtechnique)11a5.1.4 ThemechanismofCu(I)-catalyzedreactionsSurprisingly, in spite of the enormous contribution of Cu(I)-catalyzed 1,4-additions oforganometallicreagentstosyntheticchemistry,themechanismofthis importanttransformationstill remains obscure, partially due to its extremely reactive profile. The Cu(I)-catalyzed 1,4-additionofGrignardreagentsproceedsrapidlyevenat-78oC,whichisabigbarrierforobservingintermediatespecies.2Moreover,thecatalyst,reagentsandsubstratesinthereactionsystemarehighly aggregated and rapidly exchanging, further complicating themechanistic studies.9a Untilrecently,experimentalresearchhadonlyprovedtransmetallationasthefirststepforthecatalyticcycle.16Harutyunyanetal.discoveredthatincaseofGrignardreagentsamonomericLCuRX,andincaseoforganolithiumamonomericLCuRisformedupontransmetallationoftheCu(I)/Josiphoscomplex,16aOntheotherhand,thegroupofGschwindconcludedthatfororganozincreagentsand

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Cu(I)/phosphoramidite complex, the transmetallated species feature amore complex structure:L3Cu2RI.16bDespite the lack of observations of any reaction intermediates for Cu(I)-catalyzed asymmetricreactions, it is widely accepted that the stoichiometric and catalytic reaction share the sameCu(I)/Cu(III) redox mechanism, based on their similar structure and reactivity.9a Our proposedmechanism for Cu(I)-catalyzed 1,4-addition of Grignard reagents is shown in scheme 4a.16a Theaddition of Grignard reagents breaks the dimeric precatalyst Cu(I)/Josiphos complex 6 into amonomeric transmetallated species7. This species interactswith the substrate to produce theintermediate π-complex 8with an additional interactionwithMg2+ coordinating on the oxygenatomof the carbonyl group. TheMg2+is coordinated to the copper throughaMg-Br-Cubridge.Aftertheoxidativeaddition,theπ-complex8transformstoaCu(III)σ–complex9.Species8and9areinequilibriumanditsconstantdependsonthestabilityof8and9.Thiscouldexplainthecis-trans isomerization of the substrate observed during the reaction.16a Theoretical calculationscarried out for stoichiometric non-asymmetric reactions show that the Cu(III) intermediate 9shouldbeveryunstable, thustheexternalphosphine ligandmayplayapositiveroletostabilize9.10dThereductiveeliminationistheratedeterminingstepandinenantioselectivereactionsthestereochemistryisintroducedatthisstage(Scheme4a).

Scheme4.Proposedmechanismofcatalytic1,4-16and1,2-addition17

Basedonthemechanismfor1,4-additionandourexperimentaldataon1,2-addition,weproposea similar mechanism for Cu(I)-catalyzed 1,2-addition (Scheme 4b). Upon addition of Grignardreagents,thesimilartransmetallatedspecies7forms.Thisspecies7interactswiththesubstratetogeneratethefirstintermediate,anewπ-complex8’whichtheneithergoesthroughaCu(I)/Cu(III)redox mechanism or direct nucleophilic attack to yield the final product. The key to the 1,2-selectivity is the presence of the α-substituent in the enone substrate, which we believedestabilizesandpreventstheaccumulationofπ-complex8’’orthesubsequentCu(III)species.Thisdestabilization prevents 1,4-addition and favors accumulation of theπ-complexes8’, leading todirect 1,2-addition (Scheme 5).1 This proposal fits our experimental data on copper catalyzedalkylationofbothenonesandarylalkylketones(Scheme5).6

Oxidative addition

Reductive elimination

P

PCu

Br

Br P

PCu

P

PCu

Br

RMgBr

RMgBr

Ph∗∗

OCuP

Br

R

PMgBr

Ph

OCuP

Br

R

PMgBr

Ph∗∗

OR

Cu (III) 8

Cu (III) 8'

π-complex 7'

R Cu Br

MgBrO

PP

∗∗

R Cu Br

MgBrO

PP

Ph

O(a)Catalytic 1,4-addition (b)

Catalytic 1,2-addition

π-complex 7

5

6

Ph

Ph

Ph∗∗

OH

R

Transmetalation

Oxidative addition

Reductive elimination

P

PCu

Br

Br P

PCu

P

PCu

Br

RMgBr

RMgBr

Ph

O

5

6

Transmetalation

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Scheme5.Reactivespeciespossiblyinvolvedin1,2-additionpathway

5.2 AimIn order to gain more understanding of catalytic 1,4- and 1,2-addition reactions, we aimed atobservingthepotentialkeyintermediates,π-complexandCu(III)species,incollaborationwithC.OgleandS.BertzfromtheUniversityofNorthCarolinaatCharlotte.Similar to the rapid injection experiment with organocopper reagents, we performed rapidinjection of the substrate into the premade transmetallated species at low temperature, andmonitored the reaction progress by kinetic 1H NMRmeasurement. The detected intermediateswere evaluated by comparing with the library of previously reported π-complexes and Cu(III)species of organocopper reagents by Ogle’s group. For any promising intermediate,comprehensive1Dand2DNMRmeasurementwerecarriedoutforfullcharacterization.5.3 ResultsandDiscussion5.3.1 CharacterizationoftransmetallatedspeciesIn2007 the transmetallationof theCu(I)-catalyzedasymmetric1,4-additionofGrignard reagenthas been studied.16a The experiments were carried out in DCM, which is also used for thecatalysis.16aThestudyrevealedthattheprecatalystCu(I)/Josiphosligandcomplexexistsasadimerinthesolutionandformstransmetallatedspecies7and12afterbeingtreatedwithMeMgBrandMeLi,respectively(scheme6).16aMethylmetallicreagentswerethereagentsofchoiceinordertosimplify the NMR signals. Similar to the formation of organocopper reagents, the morenucleophilic MeLi leads to much better and cleaner transmetallation than MeMgBr. Adding 1equivalent of MeLi yields exclusively 12, while excessive MeLi causes dissociation of thetransmetallated complex into Josiphos ligand and CuMe2Li. When using less than 3 equiv. ofMeMgBr a mixture of free MeMgBr, Cu(I)/Josiphos ligand complex and a small amount oftransmetallatedspecies7wasobserved.However,theconversionoftheinitialcoppercomplextotransmetallatedspecies7couldberaisedbyadding3-10equivalentofMeMgBr.Nodissociationof the transmetallated species into chiral ligandandMe2CuMgBrwasobserved. In this study,7and 12 were characterized by 1H and 31P NMR. Based on the results of these and otherexperiments,thepreliminarystructuresdrawninScheme6havebeenproposed.16a

Scheme6.TransmetallatedspeciesformedwithCu(I)/JosiphoscomplexandMeMgBr(7)orMeLi

(12)

In theworkofGschwindandco-workerswithEt2ZnandCu(I)-phosphoramidite complex,aNOEsignalbetweentheethylprotonandthephosphorousatomdetectedby1D1H,31PHMBCserved

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asthefirstexperimentalevidencefortheexistenceoftransmetallatedspecies13(Figure1).16bInourstudy,ourfirstgoalwastofindsuchaprovefortransmetallatedspecies7and12.Wedecidedto perform similar experiments using various NMR techniques. In the previous study themaintransmetallated species (7)was namedas speciesA and itwas accompaniedby anotherminorspecies (unknownstructure,notcharacterised)namedasspeciesB.Foreaseofcomparisonthesamenomenclatureisusedhere.

Figure1.TransmetallatedspeciesformedwithCu(I)/PhosphoramiditeprecatalystandEt2Zn

(reportedbyGschwindandcoworkers)16b

Mostof thepreviously reportedrapid injectionNMRexperimentswereusingTHF-d8assolvent,aimingatsimplerspectraduetothereducedaggregationstateofcopperspeciesinthisparticularsolvent.11,12 However, this Lewis basic solvent is detrimental for our catalytic enantioselectivesystemandonlyleadstoracemicproducts.Therefore,DCM-d2wasselectedafterconsideringitsperformance inbothCu(I)-catalyzedasymmetric1,4-and1,2-additionofGrignardreagents. Inasimilarmanner,basedon thecatalyticperformance, two ferrocenylphosphine ligands: Josiphosandrev-JosiphoswerechosenforourNMRexperiment.First the reaction process was monitored by kinetic 1H NMR measurement, and the observedintermediates further characterized by 31P NMR, 13C NMR and various 2D NMR. One of thecomplicationsinthiskindof1HNMRmeasurementiscausedbythestrongsignalsfromthechiraldiphosphineligand,whosepeaksmaydrownoutthefaintersignalsfrompossibleintermediates.ToavoidthiswechosetofollowthereactionbylookingattheCu-Mesignalwhichisexpectedtoappearintheregionabove0ppm,whichisfreefromtheotherprotonsignalsoftheligand.Anynewly formed intermediates should have a new Cu-Me signal as well, and thus can be easilydetectedinthesamearea.OurexperimentconsistedoftheadditionofasolutionofCu(I)/ligandcomplex inDCM-d2totheGrignardreagent(MeMgBrinEt2O)inaNMRtube.Contrarytopreviouslyreportedstudies16awedecidedtousemoreconcentratedsolutions(0.05Minsteadof0.016M)andlowertemperatures(-90 or -100 oC instead of -60 oC) in order to detect the unstable intermediates. In these newexperimental conditions, the signals are generallybroader.Moreover, unlike in the report from2007,16a upon addition of Cu(I)/Josiphos ligand complex solution to MeMgBr (5 equiv.), asignificant amount of the other transmetallated species B was observed next to the expectedspeciesA (Figure 2-5).We soon realized that the ratio between Cu(I)/Josiphos ligand complex,speciesA and speciesB is dependent on the amount of Et2O present in the reactionmixture.AlthoughthereactionsolventisDCM,asignificantamountofEt2OisintroducedwhenMeMgBrisadded(itssolvent).WeobservedthatperformingtheexperimentwithoutremovingEt2O,speciesA is formed exclusively, albeit in a very small amount. Partial evaporation of Et2O allowed toobtainmoreofthetransmetallatedspeciesA(Figures2and3,spectraontheleft).However,itishardtocontroltheamountofEt2Othatisevaporated,andover-evaporation(completeremoval)ofEt2OincreasestheformationofspeciesB(Figures2and3,spectraontheright).1H,31PHMBCexperimentsallowedustorevealthestructuresofAandBpartially(Figure4):oneof the phosphorous signals (PPh2) has cross-peaks with the Cu-Me, aromatic and ferrocenylprotons, while the other (PCy2) has cross-peaks with the protons from the same Cu-Me and

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aliphatic protons. This is direct experimental evidence for the proposed structure of thetransmetallatedspecies(Figure4).BissimilarinstructuretoA.ByHMQCandHSQCexperiments(Figure5),wedeterminedtheshiftofCu-MeofAtobe-0.3and-15.33ppmin1Hand13CNMR,respectively, while the same signal for speciesB is at -0.40 and -7.70 ppm. Unfortunately, forneitherAnorB,wecoulddetectanycross-peakbyROSEYor1H,13CHMBC.

Figure2.1HNMRobtaineduponadditionofCu(I)/JosiphosligandcomplextoMeMgBr(5equiv.)in

DCM-d2at-80oC,partialremovalofEt2O(left);completeremovalofEt2O(right)

Figure3.31PNMRobtaineduponadditionofCu(I)/JosiphosligandcomplextoMeMgBr(5equiv.)

inDCM-d2at-80oC,partialremovalofEt2O(left);completeremovalofEt2O(right)

AACu-complex

AA BB

AA

B

Cu-complex

Et2O

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Figure4.1H,31PHMBCspectraobtaineduponadditionofCu(I)/Josiphosligandcomplextothe

solutionofMeMgBr(5equiv.)inDCM-d2at-80oC,partialremovalofEt2O(left);completeremovalofEt2O(right)

Figure5.HMQC(left)andHSQC(right)spectrumforAandBobtaineduponadditionof

Cu(I)/JosiphosligandcomplextoMeMgBr(5equiv.)inDCM-d2at-80oC,partialremovalofEt2O(left);completeremovalofEt2O(right)

TheobservationandcharacterizationofthetransmetallatedspecieswithCu(I)/rev-Josiphosligandcomplex and MeMgBr were even more complicated. Compared with the previous case, uponadditionofasolutionofCu(I)/rev-Josiphos ligandcomplex inDCM-d2 toMeMgBr (5equiv.withpartialremovalofEt2O)at-80oCledtoalmostcompletetransmetallationtowardsspeciesA’andB’ according to 1H NMR (Figure 6b). However, in this case species B’ appeared even in thepresenceofarelativelylargeamountofEt2O(Figure6a-c,thearrowspointtothesignalofinitialCu(I)/rev-Josiphos ligand complex). Complete removal of Et2O did not only fail to enhance thetransmetallation, but also led to the formation of multiple new species (Figure 7). Unlike theCu(I)/Josiphosligandcomplex,nocross-peakcouldbedetectedinthe1H,31PHMBCexperiments.

B

AA

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Figure6.1HNMRofCu(I)/rev-JosiphoscomplexinDCM-d2at-80oC(a),Cu(I)/rev-Josiphos

complexwithMeMgBr(5equiv.)inDCM-d2at-80oC,partialremovalofEt2O(b)andCu(I)/rev-JosiphoscomplexwithMeMgBr(5equiv.)inDCM-d2at-80oC,completeremovalofEt2O(c)

Figure7.31PNMRofCu(I)/rev-JosiphoscomplexwithMeMgBr(5equiv.)inDCM-d2at-80oC,

partialremovalofEt2O(a)andCu/rev-JosiphoscomplexwithMeMgBr(5equiv.)inDCM-d2at-80oC,completeremovalofEt2O(b)

(a)Cu(I)/rev-Josiphoscomplex

(b)Cu(I)/rev-Josiphoscomplex+MeMgBr(partialremovalofEt2O)

(c)Cu(I)/rev-Josiphoscomplex+MeMgBr(completeremovalofEt2O)

A’B’

(b)Cu(I)/rev-Josiphoscomplex+MeMgBr(completeremovalofEt2O)

(a)Cu(I)/rev-Josiphoscomplex+MeMgBr(partialremovalofEt2O)

A’B’

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Incontrast,mixingCu(I)/rev-Josiphosligandcomplexwith1equiv.MeMgBrinTHF-d8ledtoaveryclean transmetallation to species C’: -0.65 and -10.2 ppm for 1H and 13C NMR (Figure 8).Interestingly,whenwemixedCu(I)/rev-Josiphosligandcomplexwith1equiv.MeLiinbothTHF-d8andDCM-d2, the sameC’wasalwaysobtained.Unfortunately,no 1H, 31PHMBCcross-peakwasobserved.ApossibleexplanationfortheformationofspeciesC’isthattheLewisbasicsolventTHFcanremoveMg2+fromthecoordinationsphereofthetransmetallatedspeciesA’,leadingtoanewspeciesC’. This result is inagreementwith thepreviousobservation, inwhichuponadditionof1,4-dioxane (to precipitate outMg2+) the transmetallated species7 (speciesA) (Scheme5)wastransformedintospecies12(speciesC).16a

Figure8.1H(up-left),13C(up-right)and31P(bottom)NMRoftransmetallatedspeciesC’formedfromCu(I)/rev-Josiphoscomplexand1equiv.MeMgBrinTHF-d8at-80oC

5.3.2 RapidinjectionexperimentIn thepreviousstudies involvingRI-NMRof stoichiometricachiralorganocopper reagents,manyclassesofconjugatedsubstratesweretested.11Amongthose,somefailedtoformtheanticipatedintermediates, some did form stable π-complexes, and some converted into the productsgradually.11,12Weassumedthatinourcase,involvingCu(I)-complexwithchiralligand,conjugatedsubstratesthatweresuccessfulinthepreviousstudieswouldofferthehighestchancetoformπ-complexeswithtransmetallatedspeciesderivedfromtheCu(I)/chiralligand.Forthisreason,chalcone,knowntobeformingstableπ-complexwithGilmanreagents11hwasourfirstchoiceforstudying1,4-additionusingchiralCu(I)-complex.Weanticipatedthatthechemicalshifts in the NMR spectra for the hypothetical π-complex formed between chalcone andtransmetallated Cu(I)/chiral ligand complex would be analogous to that reported for the π-complexformedwithGilmanreagents(Figure9).

C’

C’

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Figure9.a)1Hand13CNMRppmvaluesreportedbyC.Ogleandco-workersforπ-complexformedbetweenchalconeandGilmanreagents;11hb)1Hand13CNMRppmvaluesexpectedforπ-complex

formedbetweenchiraltransmetallatedspeciesandchalcone

We first injected chalcone into the solution of transmetallated species of Cu(I)/Josiphos ligandcomplex at -80 oC inDCM-d2,with partial removal of Et2O fromMeMgBr. The reaction did notproceed at this temperature and no intermediates were observed. When we raised thetemperatureto-60oC,thesubstrategraduallyconvertedintotheproduct,butnointermediateswereobserved.

Figure10.Rapidinjection1HNMRexperiment:chalcone(1equiv.)injectedintosolutionof

transmetallatedspeciesofCu(I)/rev-JosiphosligandcomplexandMeMgBr(5equiv.andpartialremovalofEt2O)inDCM-d2at-80oC

Incontrast,whenusingCu(I)/rev-Josiphos ligandcomplex for thesameexperiments, thesignalscorrespondingtochalconedecreasedveryslowlyafter the injectionat -90oC.Simultaneously,anewspecieswithadoubletat5.42ppmappeared.The formation rateof thisunknownspeciesincreaseduponraisingthetemperatureto-80oC(Figure10).Comparingwiththeπ-complexesofchalcone formed with organocopper reagents, this peak could derive from a vinyl proton of a

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newly formed π-complex. However, no signal corresponding to a new Cu-Me was observed.Furthermore,nocross-signalbetweenthevinylprotonandtheCu(I)complexwasdetectedwhenusing 1H, 31PHMBC, 1H,13CHMBCor ROSEY experiments. To gainmoreunderstanding into theoriginofthisspecies,anotherexperimentwascarriedout inwhichchalconewas injected intoasolution of CuMe2MgBr, and the same signals appeared in this case. After further analysis werealizedthatthisnewpeakcorrespondstotheenolateadditionproduct.In order to study 1,2-addition of Grignard reagents to carbonyl compounds in the presence ofchiral copper complex, aldehydeswere chosen initially. The choicewasbasedonpreviousdataobtained by Ogle and co-workers for aldehyde substrate.12 They showed not only that variousaldehydesareabletofromstableπ-complexeswithorganocopperreagents,butalsothattheseπ-complexescanbeeasily identified.12b,cFor instance, thealdehydesignal in thecorrespondingπ-complex shifts dramatically fromaround10 and190ppm for in 1H and 13CNMR to5.6 and86ppm,respectively (Scheme7).Theseshiftsareverycharacteristic forthe identificationoftheπ-complex.Figure11showstheNMRshifts inppmsthatwewouldexpect forourhypotheticalπ-complexformedbetweenchiraltransmetallatedcoppercomplexandanaldehyde.

Scheme7.1Hand13CNMRppmvaluesoftheπ-complexformedbetweenGilmanreagentsand

aldehyde(reportedbyC.Ogleandcoworkers).12b,c

Figure11.1Hand13CNMRppmvaluesanticipatedforaπ-complexformedbetweenbenzaldehyde

andchiraltransmetallatedspeciesWefirstselectedo-F-benzylaldehydeand2,4-dicloro-benzylaldehydeassubstratestobeaddedtothe transmetallated species formed with Cu(I)/rev-Josiphos ligand complex and 1 equiv. ofMeMgBr,without removal of Et2O at -90 oC in DCM-d2. These two aldehydeswere among thesuccessful substrates reported in earlier studies with Gilman reagents. Unfortunately, bothsubstratesweretooreactiveforourstudy:theadditionreactionwascompleteafterthefirstfewscans.No intermediate formationcouldbeobserved.Toslowdownthereactionratewetestedthelessactivatedbenzylaldehyde,butalsointhiscasethereactionwascompletewithinminutes.

Scheme8.1Hand13CNMRppmvaluesofπ-complexformedbetweenGilmanreagentand

fluorenone(reportedbyC.Ogleandcoworkers)12a

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Next,wedecidedtousefluorenone,anevenlessreactivecarbonylcompound.FromourpreviousworkonCu(I)-catalyzed1,2-additionofGrignardreagentstodiarylketones,wewereawarethatthesesubstratesaremuchlessreactivewhencomparedtoaldehydesandarylalkylketones.7Noconversionwasobservedat-78oCwithouttheactivationwithLewisacid.Moreover,Ogleandco-workersreportedthatfluorenoneformssuchstableπ-complexwithorganocopperreagentsthatitwaspossible toobtainX-ray crystallographydata for it (Scheme8).12aHowever, comparedwithaldehydes, fluorenoneaswellas theotherketones lack thecharacteristicaldehydepeak,whichposesaproblemfortheidentificationofthereactionintermediates.Nevertheless,wedecidedtocarry out RI-NMR experiments with fluorenone as well, initially with Cu(I)/rev-Josiphos ligandcomplex. After rapid injection of fluorenone, we observed a fast decrease of both thetransmetallatedspeciesA’andfreeMeMgBr.Apartfromthis,threenewmethylsignalsappearedat -0.57, -1.17and -1.34ppm,whichalldisappearedafter2h (Figure12).Wehypothesisedthatthe signals at -0.57 and -1.34 ppm (integrating 1:1) could belong to the CuMe2-fluorenone π-complex derived from the dissociation ofMe2CuMgBr from the transmetallated chiral complexfollowedbyπ-complexformationwithfluorenone.Furthermore,1H,13CHMBC,1H,31PHMBCandHMQCexperimentsdidnotrevealanyexpectedcross-signals.

Figure12.Rapidinjection1HNMRexperiment:fluorenone(1equiv.)injectedintosolutionof

transmetallatedspeciesofCu(I)/rev-JosiphosligandcomplexandMeMgBr(1equiv.andwithoutremovalofEt2O)inDCM-d2at-90oC

We performed similar experiments with Cu(I)/Josiphos ligand complex as well. In this case nosignals corresponding to CuMe2-fluorenone π-complex were detected. Instead, a new methylsignalat-0.74appearedimmediatelyaftertheinjectionoffluorenoneandgraduallydisappeared(30min),tooshorttoallowforanyfurthercharacterizations(Figure13).

A’ MeMgBr

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Figure13.Rapidinjection1HNMRexperiment:fluorenone(1equiv.)injectedintoasolutionoftransmetallatedspeciesofCu(I)/JosiphosligandcomplexandMeMgBr(1.5equiv.andcomplete

removalofEt2O)inDCM-d2at-80oC.

5.4 ConclusionIn this study, we attempted to detect and characterize the intermediates formed in coppercatalyzed1,4-additionsaswellas1,2-additionandalkylationofketonesusingGrignardreagents.Utilizing1Hand31PHMBCNMRexperimentswewereabletocarryoutafullcharacterizationofthe transmetallated species formed upon the addition of MeMgBr to the complex ofCu(I)/Josiphos ligand.Unfortunately, the lack of a cross-signal observedbetween theMe groupand the phosphorus atom when using 1H and 31P HMBC NMR experiments, did not allow thecharacterizationofthetransmetallatedspeciesformedwithCu(I)/rev-Josiphosligandcomplex.Rapid injection NMR experiments were carried out in order to observe the π-complexintermediates formedbetween transmetallated speciesandvariouselectrophilic substrates. For1,4-addition,we tested chalcone as a substrate but no reaction intermediatewas observed. Incase of 1,2-addition, we tested aldehydes, but these substrates were too reactive and onlyaddition products were observed. Several short-lived new species were detected when usingfluorenoneasasubstrate.However,nocross-signalwasobservedby2DNMRmeasurementstoallowfurthercharacterizations.5.5 ExperimentalSection5.5.1 GeneralinformationExperimentswerecarriedoutintheUnitedStates,attheUniversityofNorthCarolina,Charlotte.NMRspectrawereobtainedwithaJEOLECA-500spectrometer.Chemicalshiftvaluesarereported

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inppmwiththesolventresonanceastheinternalstandard(CHCl3:δ7.24for1H,δ77.23for13C).Dataarereportedasfollows:chemicalshifts,multiplicity(s=singlet,d=doublet,t=triplet,q=quartet, m = multiplet), coupling constants (Hz), and integration. All NMR tubes (Norell) weredried in an oven (150 °C) and cooled under Ar. In order to get consistently good results, it iscriticallyimportantthattheNMRtubesbeunused.All chemicalswere purchased from SigmaAldrich and usedwithout purification.MeMgBr (2M)waspreparedfromMeBrandMgactivatedwithI2inEt2O.Josiphosandrev-JosiphosligandswerepurchasedfromSolvias.TheanhydrousTHF-d8andDCM-d2wasfreshlydistilledwithCaH2.5.5.2 RapidInjectionNuclearMagneticResonance(RI-NMR)

Figure14.RapidInjectionNMRsetup

The transmetallated species isprepared inaNMR tubewith its cap removedandplaced in theNMR magnet for study (Figure 14). A Dewar of liquid nitrogen is used to provide an inertatmosphere,aswellastocooltheNMRprobetothedesiredtemperature.Theinjector’ssyringeisloadedwithasolvent,andthenthesubstrateofinterestisplacedinthetipoftheglasscapillary,whichisconnecteddirectlytothesyringebarrelviaa1mLgastightsyringe.TheinjectoristhenloweredcarefullyintotheNMRmagnetandanitrogencylindergaslineisattached,whichpowersapistonintheinjectorusedtopropelthesolventandsubstratefromthesyringe.Thesubstrateisinjected into the NMR tube while its spinning is maintained in the NMR probe at lowtemperatures.Anexternal triggeronthe injectorsenseswhenthe injectionhasbeenmadeandstarts the Rapid Injection pulse sequence. This pulse sequence is unique in that it pulses andacquiresanFIDrepeatedlywithexponentiallyincreasingtimeintervalsallowingustoseehowthereaction is progressing over time. The time intervals are exponential due to the fact that thereactionprogressslowsasthereactantconcentrationsbegintodecline.

TransmetallationexperimentswithMeMgBrMeMgBr(0.075mL,0.15mmol,5equivlents)wasaddedtoaseptum-sealedNMRtubeunderAr.TheEt2Owascarefullyevaporatedundervacuumfor2h.MeanwhileJosiphosorrev-Josiphos(19.2mg,0.03mmol),CuBr.SMe2 (6.2mg,0.03mmol)and0.4mLanhydrousDCM-d2orTHF-d8wereadded toanother septum-sealed flaskunderAr.Thismixturewas stirred for5minuntil a clear

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solution formed. This solutionwas transferred to theNMR tube at -78 oC and themixturewasagitatedfor1minwithavortexmixer.Thesamplewascheckedby1HNMRat-80oC.TransmetallationexperimentswithMeLiJosiphos or rev-josiphos (19.2 mg, 0.03 mmol), CuBr.SMe2 (6.2 mg, 0.03 mmol) and 0.4 mLanhydrous DCM-d2 or THF-d8were added to a septum-sealed flask under Ar. Thismixturewasstirred for 5min until a clear solution formed. This solutionwas transferred to a to a septum-sealed NMR tube under Ar and cooled to -78 oC.MeLi (0.03mL, 0.03mmol, 1 equivlent) wasaddedtotheNMRtubeandthissolutionwasagitatedfor10swithavortexmixer.Thesamplewascheckedby1HNMRat-80oC.5.6 References1)J.Rong,T.Pellegrini,S.R.Harutyunyan.Chem.Eur.J.2016,22,3558.2)a)A.Alexakis,J.E.Baeckvall,N.Krause,O.Pámies,M.Diéguez,Chem.Rev.2008,108,2796,b)S. R.Harutyunyan,T.denHartog,K.Geurts,A.J.Minnaard,B.L.Feringa,Chem.Rev.2008,108,2824,c)F.Lopez,B.L.Feringa,inAsymmetricSynthesis,(Eds.:M.Christmann,S.Brase),2008,pp.83,d)T.Jerphagnon,M.G.Pizzuti,A.J.Minnaard,B.L.Feringa,Chem.Soc.Rev.2009,38,1039,e)F. Lopez,A. J.Minnaard,B. L. Feringa,Acc.Chem.Res.2007,40,179, f)C.Hawner,A.Alexakis,Chem.Commun.2010,46,7295,g)L.Gremaud,L.Palais,A.Alexakis,CHIMIA,2012,66,19,h)D.Mueller,A.Alexakis,Chem.Commun.2012,48,12037.3)a)Copper-CatalyzedAsymmetricSynthesis,1sted.(Eds.:A.Alexakis,N.Krause,S.Woodward),Wiley-VCH,Weinheim,2014,b)CatalyticAsymmetricSynthesis,3rded,(Eds.:I.Ojima),Wiley-VCH,Weinheim,2010,c)G.-L.Zhao,A.Córdova, inCatalyticAsymmetricConjugateReactions,3rded.(Ed.:A.Córdova),Wiley-VCH,Weinheim,2010,pp.145,d)D.Polet,A.Alexakis, inChemistryofOrganocoppercompouds(Eds.:Z.Rappoport,I.Marek),Wiley-VCH,Weinheim,2009,pp693,e)B.L.Feringa,R.Naasz,R.Imboos,L.A.Arnold,inModernOrganocopperChemistry,(Ed.:N.Krause),Wiley-VCH,Weinheim,2002,pp.224,f)FundamentalsofAsymmetricCatalysis(Eds.:P.J.Walsh,M. C. Kozlowski), University Science Books, 2009, g) Organotransition Metal Chemistry: FromBonding to Catalysis (Ed.: J. F. Hartwig), University Science Book, 2010, h) K. Tomioka, inComprehensive Asymmetric Catalysis, Suppl. 2, (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),Springer-Verlag,2004,pp.109, i)Organometallics inSynthesis:ThirdManual (Ed.:M.Schlosser)Wiley-VCH,Weinheim, 2013, j) P. Knochel, B. Betzemeier, inModern Organocopper Chemistry,(Ed.: N. Krause), Wiley-VCH, Weinheim, 2002, pp. 45, k) M. Kotora, R. Betik, in CatalyticAsymmetricConjugateReactions,3rded.(Ed.:A.Córdova)Wiley-VCH,Weinheim,2010,pp.71.4)R.Mpser,Z.V.Boskovic,C.S.Crowe,B.H.Lipshutz,J.Am.Chem.Soc.2010,132,7852.5)V.R.Madduri,A.J.Minnaard,S.R.Harutyunyan,Chem.Comm.2012,48,1478.6)V.R.Madduri,A.J.Minnaard,S.R.Harutyunyan,Angew.Chem.Int.Ed.2012,51,3164.7)P.Ortiz,A.M.delHoyo,S.R.Harutyunyan,Eur.J.Org.Chem.2015,72.8) J.Rong,R.Oost,A.Desmarchelier,A. J.Minnaard,S.R.Harutyunyan,Angew.Chem. Int.Ed.2015,54,3038.9) a) N. Yoshikai,E. Nakamura,Chem. Rev.2012,112,2339, b) A. E. King,L. M. Huffman,A.Casitas,M. Costas,X. Ribas,S. S. Stahl,J. Am. Chem. Soc.2010,132,12068, c) A. E. King,T. C.Brunold,S. S. Stahl,J. Am. Chem. Soc.2009,131,5044, d) J. A. Mayoral,S. Rodriguez,L.Salvatella,Chem.Eur.J.2008,14,9274,e)S.Woodward,Angew.Chem.Int.Ed.2005,44,5560,f)V. Grushin,H. Alper,J. Org. Chem.1992,57,2188, g) D. H. R. Barton,D. M. X. Donnelly,J. P.Finet,P. J. Guiry,J. Chem. Soc. Perkin Trans. 1,1991,2095, h) E. Nakamura,S. Matsuzawa,Y.Horiguchi,I. Kuwajima,Tetrahedron Lett.1986,27,4029, i) E. J. Corey,N. W. Boaz,TetrahedronLett.1985,26,6015.

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