nature chem[1].(Zhang-Jie Shi)(4)

施老师的代表作

ARTICLES

transition-metalcatalystsindifferentconcentrations(Fig.2).Theexponentialdecayofla-Brandformationof3aawereobserved,indicatingthezero-orderdependenceondifferentmetalcatalysts(Fig.2).Ontheotherhand,theuseofcommerciallyavailablesub-limedKOt-Bu(Aldrich)andotherdifferentsourcesofKOt-Buand1,10-phenanthrolinedidnotdramaticallyaffectthereactionoutcome.Wealsorepeatedtheexperimentswithnewglassware,andeventooktheextremestepofhavingotherlaboratoriesrepeatthereactionsandcon rmthereliabilityofourobservations.

Ultimately,weconcludedthatthereactionratewas,infact,notrelatedtotheconcentrationofanytransition-metalcomplex,andthattransition-metalcomplexeswerenotinvolvedinthiscross-couplingreaction.Tothebestofourknowledge,thiswasthe rstexampleofahighyieldcross-couplingbetweenarylhalidesandbenzeneintheabsenceofadditionaltransitionmetals(webecameawareofsimilarresultsfromotherlaboratorieswhilethismanuscriptwasinpress45).Thistransition-metal-freeprotocolpotentiallysolvesthechallengingproblemofheavymetalremainingin nalproducts.Ontheotherhand,recentreportsontransitionmetal-catalysedcross-couplingbetweenaryliodidesandarenessuggestthatthemetal-freeconditiondevelopedherelikelyoccursthroughacomple-telydifferentreactionmechanism16,24,28,31,46,47.

Toexplorepotentialapplicationsofthismethod,avarietyofaro-maticiodides(ArI)wereinitiallyexamined(Table2).Electron-donatingsubstituentsonthephenylringofArI,suchasmethoxylandmethylgroups,promotedthecross-couplinginhighef ciency,andthedesiredproductswereisolatedingoodtoexcellentyields.Thesubstitutionpatternmadelittledifferencetothereactionoutcome(3aa,3ba,3ca,3eaand3ga).Polysubstitutedelectron-richaryliodidesalsoworkedwell(3ha).4-Chloro-1-iodobenzeneand4- uoro-1-iodobenzenewerealsotested,andthecorrespondingcouplingproductswereisolatedinexcellentyields,leavingthe uo-rideandchloridesubstituentsuntouched(3la,3ma).TheseresultsnotonlyindicatethecompatibilityofC–FandC–Clwiththereactioncondition,butalsoofferanopportunitytofurtherfunc-tionalizetheproductsthroughsequentialorthogonalcross-coup-lings.4-Bromobiphenylgaveanexcellentyieldoftheterphenylproduct(3ja).Someelectron-de cientaryliodideswerenotgoodsubstratesforthisreaction.Forexample,1-iodo-3-tri uoromethyl-benzeneand4-iodobenzonitrileshowedonlymoderatereactivityunderthesameconditions(3na,3oa).1-Iodo-4-tri uoromethoxy-benzene,however,didcouplewithanisolatedyieldof89%(3ka).Naphthylandheteroaryliodidesalsounderwentthistransformationsmoothlyandgavegoodyields(3qa,3ra).

Underoptimizedconditions,variousarylbromides(ArBr)werestudied(Table2).Aswiththeiodidecouplings,electron-donatingsubstituentswerebene cialforthistransformationinmostcases(3aa,3da,3ea,3fa,3haand3ia).Thetransformationwasalsosen-sitivetostericeffects.Forexample,2-bromotolueneexhibitedmuchlowerreactivity(3ga).Incontrasttoaryliodides,electron-de cientarylbromidesexhibitedhigherreactivity,althoughinsomecases

OBr4

H

5, isolated yield: 73%

NATURECHEMISTRY

DOI:10.1038/NCHEM.862

Figure4|Proposedinteractionsbetweenthephenanthroline,baseandsubstrateforthistransitionmetal-freecross-coupling.InthepresenceofKOt-Buand1,10-phenanthroline,both1,10-phenanthrolineandKþionsmightinteractwiththearenesubstratethroughp,p-stackingaswellasion–pinteractionstopromotethereactivityofthebenzene.

onlymoderateyieldswereobtained(3oa,3pa).Variousfunctionalgroupswerefoundtobecompatible,suggestinggreatpotentialforfurthertransformationofthecross-couplingproducts.Onceagain,heterocyclicsubstrateswerefoundtobesuitablesubstrates(3sa,3ta),providinganumberofpotentialapplicationsinsyntheticchemistry.Inaddition,thedoublecouplingalsotookplacesmoothlywheneither1,4-diiodobenzeneor1-iodo-4-bromoben-zenewereusedassubstratesandthedesiredterphenylwasisolatedinmoderateyields(3ja,46%using1,4-diiodobenzeneand35%using1-iodo-4-bromobenzene).

Wefurtherexploreddifferentarenes(C–H)couplingpartners(Table2).Notably,theenhancementofC–Hbondaciditydramati-callyimprovedef ciency.Forexample,1,4-di uorobenzeneshowedmuchbetterreactivity,andthedesiredproduct(3ac)wasobtainedwithboth4-bromo/iodoanisole.Withincreasedelectrondensityinthearenes—forexample,inthecasesoftoluene,xylenesandanisolederivatives—lowef cacywasobservedunderstandardconditions(3ad–3ah).Increasingthereactiontimeandtemperature,however,restoredthereactivity.Underoptimizedconditions,eventhehighlystericallyhinderedmesitylenecouldbefunctionalizedinmoderateyield(3ab).Inthereactionsofelectron-richarenes,wenotedthatcouplingtothemeta-position(relativetotheelec-tron-donatinggroup)dominated;when1,1,1-tri uorotoluenewasusedasacouplingpartner,themeta-arylatedproductwasobservedasmajorproduct(3aj),whileotherelectron-de cientarenessuchasbenzonitrileandethylbenzoateshowedpoorreactivity.ThisresultmightindicatethepotentialinteractionbetweenthebaseandC–Fmoietyofthetri uoromethylgroup.Alltheseresultsindicatethatthereactionpathwayisdifferentfromtheconventionaltransition-metal-catalysedC–Htransformations,whichfurthersupportsthemetal-freereactivity.Notably,whenthenitrogen-containinghetero-cycleswereapplied,onlyoneisomerofthedesiredcross-couplingproductswasobtained(3al).Althoughahigheref ciencyinthisreactionwouldbedesirable,thepotentialforcouplingheterocycliccompoundsishighlyappealing.

Wealsoinvestigatedanintramolecularversionofthereactionbycarryingoutacyclizationusing1-(benzyloxy)-2-bromobenzeneasthesubstrate.Therelativelylowreactivityofmesitylenemeansthatitcanstillbeusedassolventforthereaction.Toourdelight,thecorrespondingintramolecularcouplingproduct6H-benzo[c]-chromene5wastheexclusiveproduct,whichweobtainedin73%isolatedyield(Fig.3).Thisresultsuggestsapromisingapplicationintheformationoffusedringsystems.

Discussion

Veryrecently,Itamiandothershavereportedaninterestingcross-couplingbetweenarylhalidesandheterocylcesinthepresenceofKOt-Buandabsenceoftransitionmetals48,49.Intheirstudies,thearylradicalwasconsideredtobethekeyintermediateinitiatedbyKOt-Buandassistedbyheterocycles.Inourcase,weproposetheradicalisinitiatedfromthearylhalideswithKOt-Bu.Itisproposedthatthephenanthrolinemightplayasimilarroletotheheterocycles

NATURECHEMISTRY|ADVANCEONLINEPUBLICATION|http://www.77cn.com.cn/naturechemistry

Figure3|Metal-freeprocessintheintramolecularcross-couplingtoprepare6H-benzo[c]chromene.Thereactionwascarriedoutinthe

presenceof1,10-phenanthroline(0.5mmol,40mol%),KOt-Bu(1.5mmol,3.0equiv.),mesitylene(4ml)and1-(benzyloxy)-2-bromobenzene(0.5mmol).ThereactionwasstirredunderaN2atmosphereat1008Cfor20h.

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