Catalytic conjunctive cross-coupling enabled by metal-induced metallate rearrangement.docx

1、RESEARCH|REPORTSconsistentwithalltheexperimentalevidence.Weexpect(hesame-strengthisotopeeffectifthe2Dcrystalsarccombinedwithotherprotonconductorsbasedonoxides(13.25-28),andtheseparationfactorshouldbeevenlargerlorproion-conductingmediawithstrongerhydrogenbonds：forexample,influorides(28).Theaboveexpla

2、nationallowsforseveralobservationsaboutprotontransportthrough2Dcrystals.First,itpartiallyexplains(hedisagreementbetweentheexperiment(5)andtheory(5,8-10)intheabsolutevalueofE»lorgraphene:Zero-pointoscillationsreducetheactivationbarrierby=0.2eVcomparedlotheoreticalvalues.Wespeculatethattheremaini

3、ngdifferences<20%in(hecaseof(8)Jmaybeaccountedforbyconsideringothereffectsofthesunoundingmedia(forexample,two-bodyprocessesinvolvingadistortionoflheelectroncloudsbyprotonsresidingattheNafion-graphcncinterface).Second,theexperimentsconfirmthathydrogenchemisorptionto2Dcrystalsisnotthelimitingstepin

4、thetransferprocessbecause,otherwise,theisotopeeffectwouldbedifferentforhBNandgraphene.Thirdjhedescribedsievingmechanismimpliesa=30fortritium-hydrogenseparation.Fourth,itisquiteremarkablethatzero-poinioscillations,apurelyquantumeffect,canstilldominateroom-temperaturetransportpropertiesofparticles4000

5、timesheavierthanelectrons.Theobservedlargeacomparesfavorablywithsievingefficienciesof(heexistingmethodsforhydrogenisotopeseparation(15-20).Thehighprotonconductivityexhibitedbygrapheneandboronnitridemonolayers,comparabletothatofcommercialNationfilms(5.22).makesthempoieniiallyinterestingfbrsuchapplica

6、tions.In(hisrespect,theincreasingavailabilityofgraphenegrownbychemicalvapordeposition(CVD)(29.30)providesarealisticprospectofscalingupthedescribeddevicesfrommicrometersizes(othoserequiredforindustrialuses.Indeed,althoughmicroinechanicalcleavageallows2Dmembranesofhighestquality,theapproachisnotscalab

7、le.Asaproofofconcept,werepeatedthemassspcctronictrj'measurementsusingccntimetcr-sizcdmembranesmadefromCVDgrapheneandachievedthesamea=10(fig.S7).Notably,thisshowsthatmacroscopiccracksandpinholespresentinCVDgraphenedonotaffectlheefficiency,becausehydronsareelectrochemicallypumpedonlythroughthegrap

8、heneareaslhaiareelectricallyconiacied(22).Furthermore,weestimatetheenergycostsassociatedwiihthisisotopeseparationmethodas=0.3kWhperkilogramoffeedwater(22),appreciablylowerthancostsoftheexistingenrichmentprocesses(15,16).Allthiscomesontopofthefundamentallysimpleandrobustsievingmechanism,potentiallysi

9、raighilbrwardsetups,andtheneedforonlywaterattheinputwithouttheuseofchemicalcompounds(16).REFERENCESANDNOTESJ.S.Bunchetal.NanoLett.8.2458-2462(2008).S-P.Koenig,I.Wang,J.Pellegrino,J.S.Bunch,Nat.Nanolechnol.70Iccnacrts,B.Partocns,F.MPorters,Appl.PhysLett.93,23.K193107(2008).24.K.W.RHndcl,S.H.Bcrgcns,R

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11、Nardelli,QWang,Y.Liu,PhysChem.25.T.Hibino,K.Meutani,H.Iv/ahara,J.Electrochem.Soc.140.2538(1953).26. K.D.Feuer,Chem.Mater.8.610-641(1996).27. D.Marx.M.E.Tuckerman,J.Hutter,M,Parrinello,Nature9.M.Miao,Chem.Phys.15z16132-16137(2013).28.D.Marx.ChemPhysChe10.J.L.Achtyletal.rNat.Commun.6,6539(201S).29.A.R

12、einaetal.Rev.55,713-743(1955).30K.$.Kimctal.Nature457,706-710(2009).12. BE.Conway,Proc.R.Soc.AMath.Phys.Eng.Sei.256,128-144(I960).ACKNOWLEDGMENTSK.D.Kreuer.A.Fuchs,J.Maier,SolidStateIon.77,1S7-162(19951397,601-604(19)9).n7,1&U-1870(2006).ManoLett.9,30-35(2009).11.K.B.Wiberg,Chem.Thisworkwassuppo

13、rtedbytheEuropeanResearchCouncil,A.Parisetal.Adv.Funct.Mater.23.1628-1635(2013.Lloyd'sRelisterFoundation,theGrapheneFlagship,theRoyal14. H.K.RaerEd.rSeparationofHydrogenIsotopes(ACSSociety,theASymposiumSeries.Washington.DC,1978).ofNavalResearch.15. A.I.Milter.Can.Nucl.Soc.Bull.22,1-14(2001).prov

14、idedV.0.Borman,S.Y.Krylov,Chcm.Phys-Lett.rForceOfficeofScientificResearch,andtheOfficeM.L.-H.acknowledgesaPh.O.studentship>ytheConsejoNacionaldeCiendayTecnologia17.J.J.M.Beenakkec,Mexico)Thereputedresultsareincludedinapatentapplication232,379-382(199S)*Qrapj>ene.pf0l0nTransport,*whichismostX.Z

15、hao,S.Villar-Rodd,A.J.Fletcher,K.M.Thomas,J.Phys.Chem.110.9947-9955(2006).SUPPLEMENTARYMATERIALSB.E.Conway,Proc.R.Soc.LondonScr.A247,400-419wv/v/.scienMaterialsaJ.H.Rolston,J.DenHartog,J.PButler,J.Phy5.Chem.80,/content/351/6268/68/suppl/DCl(1958).»dMethods(1976).Figs.SItoS71064-10675(31

16、-49)RefcrencJ.B.Marling,I.P.Herman.S.J.Thomas,J.Chem.Phys.72,560J-5634(19S0|.8July2015;accepted18November201521. SeesupplementarymaterialsonScienceOnline.10.1126/cience.aac9726ORGANICCHEMISTRY/ecross-couplingCatalyticconjuncthenabledbymetal-inducedmetallaterearrangementLiangZhang,GabrielJ.I.ovinger,

17、EmmaK.EdelsteiiMatteoP.Chierchia,JamesP.Morken*,AdatnA.Szymaniak,mporaryorganicsynthesis.ConsideringtheTransitionmetalcatalysisplaysacentralroleincontetremendouslybroadarrayoftransitionmetal-catalyzedtransformations,itisremarkablethattheunderlyingelementaryreactionstepsarerelativelyfetheorganometall

18、ictransmetallationstepthatiscommoninmanymetal-catalyzedreactions,suchasSuzuki-Miyauracoupling.Specifically,wedemonstratethatvinylboronicesteratecomplexes,preparedbycombiningorganoboronatesandorganolithiumreageirearrangementwherein1,2-migrationofanalkylorarylgroupfromborontothevinyla-carbonoccursconc

19、omitantlywithC-Pds-bondformation.Thiselementaryreactionenablesapowerfulcross-couplingreactioninwhichachiralPdcatalystmergesthreesiriplestartingmaterialsanorganolithium,anorganoboronicester,andanorganotriflateintochiralorganoboronicesterswithhighenantioselectivity.winnumber.Here,wedescribeanalternati

20、vetonts,engageinpalladium-inducedmetallateOrganoboronicacidsandtheirderivativestion.Themostcommonlypracticedsuchreactionarewidelyavailableandbroadlyusefulisthetransitionmctal-calalyzedSuzuki-Miyaurastartingmaterialsfororganicandreactivity.Althoughchemicallyandconfigurationallystable,organoboronicest

21、ersengageinabroadarrayofcarbon-carbonandcarbonheteroatombond-formingprocessesuponactiva-synthesiscross-couplingreactionbetweenorganicclcctro(l).Inadditiontobeingenvironmentallyphilesandorganoboroncompounds(2).Inbroadbenignandgenerallyinexpensive,thesestrokes,themechanismoftheSuzuki-Miyaurarereagents

22、exhibitanear-idealbalanceofstabilityactioninvolvesDepartmentofChemistry,BostonCollege,ChestnutHill,ma024(7,ofoianoboroncross-couplinglhaiwetermUSA.,Correspondingauthor.E-mail:morkenbc.cdu"conjunctivecross-coupling”(Fig.IA)bccauscitmcrgcsbetweenametalcatalystandtheelectrophile,(ii)asequenceof(i)

23、oxidativeadditiontransineiallationwith(heorganoboronreagent,and(iii)reductiveeliminationoftheC-Cbondedproduct(3).Here,wcusedanalternativepathwaytotheorganoborontransmetallationstep.CatalyticEnantioselectiveConjunctiveCross-CouplingORR1-BORC(sp2)-XcatalystRO、§,ORsimple,monofunctionalstc versatil

24、echiralorganoborcefficientreactionwithhigh1,2-metallateshifttosp3centers"ate"complexTheoverallputativecatalyticcycleenablesaclassRESEARCH|REPORTS1.Metal-inducedmetallateshiftasastrategyforcatalyticFi&reactiondesign.(A)Thecatalyticconjunctivecross-couplingpro:ess.(B)Commonmetallateshi代t

25、osaturatedcarboncen:ersrequiresaleavinggroup.L,ligand.(C)Metallateshiftnsaturatedcarbonsisoftenactivatedbyadditionofanrtingmaterialsnicesterproductenantioselectivitytoiexternalelectrophile.M,metal;E,electrophile.(D)Ameallateshiftpromotedbyametalcomplexcanserveasanalternativetoatransmetallationproces

26、s.(E)Proposedcat;lyticcycleforconjunctivecross-coupling.Ar,arylgroup.sideredthatanelectrophilicpalladiumcomplex(II,Fig.IE).generatedbyoxidativeadditionofIwithanorganicelectrophile,mightinducel,2-inigrationinavinylboronatc-derivcdatecomplexandestablishanewC-Cbondandaboron-substiiuicdstcrcogcniccenter

27、.SubsequentreductiveeliminationwouldservetoestablishasecondC-Cbond,releasetheproduct,andconcomitantlyfurnishareducedPdcomplexthatmightcontinueacatalyticcycle.Thenetreaction,inthiscycle,isalignedwithimportantworkfromMurakami,whostudiedreactionsofalkynylboronatecomplexes(17).Althoughp-acidiclatetransi

28、tionmetalcomplexesarewellknownioactivatealkenesfornucleophilicattack,nucleopalladationwithPd(II)complexesgeneratedbyoxidativeadditionreactionsarelesscommon(18,19).Fortheenvisionedprocesstobesuccessful,severalkeyquestionsemerged:WouldthePd(ll)arylcomplexesbesufficientlyp-acidictofacilitatemetallatere

29、arrangementWouldcommondirecttransmetallation(III->V)dominatethereactionandfurnishSuzuki-Miyauraproducts?mentPdPIIelectrophile-induced1,2-metallateshifttosp2centersK、AkA=C,N,Ometal-incucedmetalliiferearrange(pPJmetal-induced1,2-metallaterearrangementMJArPPdconjunctivecouplingPcycleJpPIIItrans'

30、rPp(jdmetallationVp<7or®<PAIV；conjunctive:couplingAr-RorSuzuki-Miyaura:products:ArRESEARCH|REPORTStwonuclcophilicrcagcntsintooncduringlhccourscofthereaction.Overall.theconjunctivecross-couplingconstructschiralproductsbymergingthreesimplestarlingmaterials:anorganolithiumreagent,anorganobor

31、onicester,andanorganicelectrophile.Thereaction,whichaddstorecentcatalyticalkenecarboborationreactions(4,5),establishestwonewcarbon-carbonbondsandformsastereogeniccenterbearingausefulorganoboronicesterwithhighenantioselectivity.Organoboronicestersareknown(oparticipaieinawiderangeofreactionsthatoccurb

32、ystereospecific1.2-mctallaterearrangements(6.7).Thepreponderanceofthesereactionsoccurwithafour-coordinateanionicboron-centered"ate"complex(Fig.IB)thatrearrangesbya1,2-carbonshiftfromborontoanadjacentsp'-hybridizedelectrophiliccenter(designated"A")bearinganattachedleavinggroup

33、(X).Thestcrcoclcctronicrequirementsofthemetallateshiftdictateananti-periplanararrangeineniofthemigratingcarbonatom(R)andtheleavinggroupsuchthattheoverallprocessisstcrcorctcntivcatRbutstcrcoinvcrlivcatA(8).Theseprocessesarecommon(9)foriranslbmialionswherethe"A"groupisacarbon,niirogen,oroxyg

34、enatomandlesscommonbu(stillestablishedforsulfurandphosphorus(10,11).Becauseofthestereospecificnatureoftheabovedescribedprocesses,stereoselectivityinmetallateshiftsisgenerallysubjecttosubslralccontrol(12).althoughJadhavandManreportedanexamplewithselectivitydictatedbyachiralcatalyst(13).Metallaterearr

35、angementfromborontosp(14)andsp，(15)hybridizedcarbonsoftenrequiretheadditionofanexternalelectrophilicactivator(Fig.IC),andgenerallythe1,2-metalIateshiftisfollowedbyeliminationloreestablishunsaturation(16).In(hiscontext,weconsideredthatinplaceofstoichiometricelectrophilicactivatingagents,p-acidiclatet

36、ransitionmetalsmightsimilarlypromotethe1,2-metallateshiftofalkenylboronates(Fig.ID)andthattheresultingchiralorganometallicintermediatemightbeusedinsubsequentbond-fbrmingprocesjtes.Inoneembodimentofcatalysisbasedonmetalinduced1,2-metallaterearrangements,wecon-SCIENCEsciencemag.oiFig.2.Scopeofthecatal

37、yticconjunctivecross-couplingreactionstartingfromvinylboronicesters.Yieldsrepresentisolatedyield1JANUARY2016VOL351ISS(E6268711:83%yield2:66%yield3:77%yield97:3er93:7er98:2er4:74%yield88:1298:2er5*:48%yielderOMeMeMe'BTHF,60°C,14thenNaOH,H2(|)21%Pd(OAc)21.2%(SPSP)-L1R2OTfOHPhMeOMe(SpSglNMe2Me

38、fP<-OMeMeNMe2OHk,PhQHQH6:68%yield7:84%yield8:QHpurifiedmaterialandareanaverageoftwoexperiments.Theabsoluteconfigurationwasdeterminedbyanomalousdispersionx-rayandbychromatographiccomparisontoknowncompounds.*VinylB(neo)wasreplacedwithvinylB(pin);treactionconductedat80°C.erwasdeterminedbychiral

39、supercriticalfluidchromatography.OAc,acetate;Me,methylgroup;Ph,phenylgroup;OTf,trifluoromethanesulfonate;OTBS,tertbutyldimethylsiloxy.11:49%98:296:4eryielderhexyl70:30er12:83%yield98:2erOHhexyl17*:74%yield94:6er16*:73?.yield87:1C0>O51%yield9f:51%yieldMe10t：44%yieldMe97:3er97:3er94:6erMehqMQHOMeCH

40、OOMeOMe95:5er15*:86%yield97:3er13:68%yild14*:73%yield96:4er18*:50%yield89:11erCHx0TBS19:46%yield93:7erCO2Me20*:41%yield90:10erCouldfacialselectivityinolefinbindiigrenderthemigration(IIIIV)cnanliosclcctivc?Last,wouldb-hydrog<neliminationinintermediatessuchasIVcompetewithreductiveelimination?Tobegi

41、nourstudiesoftheconjunctivecr)sscouplingreaction,weselectedphenylirflateastheelectrophile,anticipatingthattheouter-spheretriflateanionwouldleaveopenacoordinationsiteonPdforalkeiebinding(Fig.IE,III).Inaneffortminimizestericpenaltiesthatmightinhitmetallateshift,weoptedforanunsubstituu<1oitvinylgrou

42、pinconstructionoftheboronaecomplex.Similarly,onthebasisofrecestudiesfromMayrandAgganval(20.21weselectedaneopentylglycolatoligandt>1boronbecausetheatecomplexesderiv<dfromthisligand(versusothersrcadiavailable)weredeterminedtobethemostnucleophilic.Last,inanefforttofav)rreductiveeliminationrelativ

43、elob-hydrogdneliminationinputativeintennediateIV.vselectedligandswithlargebiteanglesfortlepalladiumcomplex.Initialexperimentswiachiralbidentateferrocenyl1,1diphosphineswerepromisingandsuggestdthattheconjunctivecross-couplingcouindeedoperate.AsurveyofanumberchiraldiphosphincstructuresrevealedthitJosi

44、phos(22)andMandyPhos(SolviasAG,Kaiseraugst,Switzerland)(23)particularlyeffectiveligandclasses,withtieMandyPhosligandLIproviding<ndverygoodcatalystefficiencyinthereactioi.botharylandalkylgroupsprovedcompetentmigratingelementsinconjunctivecouplingreactions.Incaseswheretheyieldofproductislow,analysi

45、softhereactionmixturebeforeoxidationshowedthatby-productsgenerallyconsistofrecoveredorganoboronicester(likelygeneratedduringworkupbyprotonolysisofonecarbonligandfromtheatecomplex)anddirectSuzuki-Miyauraproducts.Primarj-andsecondaryalkylgroupsmigrate,asdofunctionalizedalkylappendagesc.g.(triniclhylsi

46、lyl)nicthylj.Conjunctivecouplingswerealsoeffectiveforbothelec(ron-richandeleciron-poorelectmphiles.Moderatelyencumberedelectrophiles,suchasorlho-subslitutcdarenes,canengageinthereaction,althoughthemorehighlysubstiuned2,6-dimethylphenylderivativesufferedfromlowerselectivity.Withrespecttopreparationof

47、chiralhydrocarbonframeworks,arangeofsubstitutedalkenyltriflaiesparticipate,andtheconfigurationoftheproductalkenedirectlyreflectsthatoftheprecursorelectrophile.outstandinglevelofenantioseleclivityarInoptimizingthereactionconditions,vefoundtetrahydrofuran(THF)(obethemo4effectivesolvcnl.Therefore,whent

48、lcmigratoryRgroupwasappendedtoboronIadditionofhydrocarbonsolutionsorganolithiumreagentstotheneopentglycol-derivedvinylboronicestvinylB(neo)(Fig.2),theresultingy，icomplexeswereevaporaiediodrynessarredissolvedinTHFbeforereaction.Theefficiencyofthereaciionwasalsogrea(diminishedbychloride,bromide,oriodi

49、ceions,anobstacleeasilyovercomebyilecontinueduseofarylandalkenyltriflatcsistheelectrophile.Forcouplingofalkeninflateelectrophiles,thereactionsclcctiviwasmarkedlyenhancedwithboronaecomplexesderivedfrompinacolatoligandsinplaceoftheneo-pentylglycoiderivati|duct15isformedin53%yieldar82:18enantiom

50、ericratio(cr)whenusingtlcneo-pcntylglycolligand),whereasforarinflates,theneo-pentylglycolligar，'lfurnishedhigherselectivity11formedin14%yield.93:7crusingB(pin)group).Withthe；cfeaturesoptimized,thescopeoftleconjunctivecouplingwasexploredwith;narrayofatecomplexesandelectrophiles.Duringtheseexperim

51、ents,i(wasmositheprodu:tconvenienttooxidizeorganoboronicesteriothederivedalcoholtytreatmentwithNaOHandHQ?;howevcr,isolationoftheorganoboronproductitselfalsopossible(theorganoboronprecursorISoalcoholIwasisolatedin76%yieldbysili(agelchromatography).AsshowninFig.RESEARCH|REPORTSTheatecomplexcouldbegene

52、ratedcilhbyadditionofanorganolithiumreagentvinylB(nco)(Fig.2)orbyadditionLTo)fMeMe。OMen-Bu/-BuCy3:76%yield21:59%yield84%yield22:80%yield23:93%yieldFig.3.Scopeofthecatalyticconjunctivecrosscouplingreactionstartingfromalkylorarylboronicesters.Yieldsrepresentisolatedyieldofpurifiedmaterialandareanavera

53、geoftwoexperiments.Cy,cyclohexylgroup.OH顷5MeMeMeMeLi®2%Pd(OAc)22.4%(SpS-LlPhOTfTHF,60°C,14thenNaOH,H202(SpSp)-L1NMe2XR°-PRESEARCH|REPORTS98:2er99:1er97:3er95:5er99:1erOHOHOHMeOPhMeOMeOF3CCIOMe24:77%yield25:83%yield94:6erO.H27:66%yield6:<5%yield97:3e-97:3erMeOH28:75%yield95:5er30:86

54、%yield95:5erNMe29:86%yield95:5erMe31:67%yield97:3erMe32:3%yield7：!:28erarrayoforganoboronicestersthatarcalreadyavailableforuseincommoncross-couplingprocesses,thelatterstrategyisparticularlyenabling.Inthiscontext,wcfoundthatthepresenceoflithiumhalidesalts,evenat1to2molepercent(mol%)lo<iding,market

55、llyenxlesconjunctivecouplingefficiency.Thus,toperformthereactionwithhighestefficiencywith2mol%catalystloading,itiscriticalthathidide-freevinyllithiumbeused.Topreparethisreagent,wedevelopedaprocedurethatinvolvedlitliium-halogcnexchangeHitlizbBuIj(Bu,butylgn)up)inhexane,followedbylow-temperaturerecrys

56、tallizationofpurevinyklithium.Whentheseprecautionsarctaken,conductingthereactionasinFig.3allowedthescopeofthemigratinggrouptobesurveyedmorecompletelyandrevealedthat,althoughreactionsrequiringmigrationofveryelectron-deficientgroupsarestillachallenge,electron-neutralandelectronricharenescanengageinthe

57、migration,ascanthosethataremorehighlysubstituted(i.e.,2,6-disubstitutedarenes).Wealsofoundthat,with5mol%catalystloading,vinyllithiumpreparedasabovebutwithoutrecrystallizationwaseffective(e.g.,3formedin69%yield,98:2er)andthatvinyllithji(24)couldb(AthenNaOHHQ1%Pd(OAc)21.2%(SpSp)-LlTfO、MeOOTBSiOMe：Fig.

58、4.Synthesisandmechanisticstudies.(A) Synthesisofcom-bretastatinbyconjunctivecross-coupling.(B) Thestereochemicalcourseofmetal-inducedmetallaterearrangement.dr.diastereomericratio.:MeO/1%Pd(0Ac)2B(neo)i.2%(SpSp)-L1jCLkciJformedin83%yield,97:3er).Toprobetheutilityofconjunctivecrosscouplingtopracticalorsanicsynthesis,wewereB(pin)MeOOMeMeOMeO(n-Bu)combretastatin97%yieldTHF,60°C,14hthenNaOH.H?O?80%yield95:5erDH34:57%yield；82:18er.>20:1dr-vinyliilhiumtoorgano