1331351361371371371381401401411411421431431431441451461461491501511531541541541551571581581591591591591591591595.2.FukuyamaReactions5.2.1.PdonCarbon(Pd/C)5.2.2.Pd(OH)2onCarbon(Perlman’sCatalyst)5.3.Pd/C-CatalyzedNegishiReactions6.Ullmann-TypeCouplingReactions6.1.Pd/C-CatalyzedAryl−ArylCoupling6.2.Pd/C-CatalyzedHomocouplingofVinylHalides6.3.Pd/C-CatalyzedIntramolecularCouplingofArylandVinylHalides7.HomocouplingofArylboronicAcids,Pyridines,andAlkynes7.1.Pd/C-CatalyzedHomocouplingofArylboronicAcids(Suzuki-TypeHomocoupling)7.2.Pd/C-CatalyzedHomocouplingofPyridines7.3.Pd/C-CatalyzedHomocouplingofAlkynes(Glaser-TypeCoupling)8.OtherCouplingReactions8.1.CyanationofArylBromides8.2.Carbonylations8.3.R-ArylationsofDiethylMalonate8.4.ArylationsofAromaticCompounds8.5.Allylations8.6.IntermolecularHeck-TypeCoupling9.PdonSolidSupportinTandemReactions9.1.SonogashiraCouplinginTandemReactions9.2.HeckCouplinginTandemReactions10.ConclusionsandPerspectives11.Abbreviations12.Acknowledgments13.References1591591601601611611621621621621621641641641641651651661661671671681691701701701.IntroductionHomogeneouspalladiumcatalysishasgainedenormousrelevanceinvariouscouplingreactionssuchasHeck,Stille,Suzuki,Sonogashira,andBuchwald-Hartwigreactions.Manyproductscouldbesynthesizedbythismethodologyforthefirsttimeorinamuchmoreefficientwaythanbefore.Thistypeofcatalysisprovideshighreactionrateandhighturnovernumbers(TON)andoftenaffordshighselectivitiesandyields.ThepropertiesofsuchPdcatalystscanbetunedbyligands,suchasphosphines,amines,carbenes,diben-zylideneacetone(dba),etc.Properliganddesignhasledtocatalyststhattolerateweakleavinggroupssuchaschloride,exhibithigherTONandreactionrates,haveimprovedlifetimes,andaresuitablystabletorunthereactionswithouttheexclusionofwaterorairandatlowertemperatures.The
10.1021/cr0505674CCC:$65.00©2007AmericanChemicalSocietyPublishedonWeb12/21/2006134ChemicalReviews,2007,Vol.107,No.1LunxiangYinwasborninAnhui,China.HereceivedhisB.S.andM.S.inchemistryatShandongUniversity(China)in1987and1990,respectively.ThenheworkedasalecturerinCollegeofShandongLightIndustryandShandongNormalUniversity.In2001,hejoinedProf.Liebscher’sgroupatHumboldtUniversity,Berlin(Germany),asaPh.D.student.Hisdoctoralresearchfocusedon“SynthesisofnewcalcineurininhibitorsbyPd-catalyzedcross-couplingreactions”.Heearnedhisdoctoraldegreein2005,andheiscurrentlyemployedasapostdoctoralresearcheratUniversityofCalifornia,Davis.Hisresearchinterestsincludetransitionmetalmediatedcouplingreactions,heterocyclicchemistry,anddevelopingnewsyntheticmethodology.Ju¨rgenLiebscherfinishedhisstudiesatTechnicalUniversityDresden,Germany,andreceivedhisPh.D.andhabilitationtherein1974and1977,respectively.HeworkedatAddisAbabaUniversityinAddisAbaba,Ethiopia,asAssociateProfessorfrom1979to1982.HejoinedDepartmentofChemistryatHumboldt-University,Berlin,asDozentin1982andbecameProfessortherein1992.HewasvisitingprofessoratUniversityWu¨rzburg,Germany,UniversityofTexas,Austin,AcademiaSinicaTaiwan,AddisAbabaUniversity,andUniversityofBotswana.Hisresearchinterestscomprisesyntheticorganicchemistry,heterocycles(synthesis,ringtransformations,applicationastoolsinorganicsynthesis),asymmetricsynthesis,analoguesofnaturalproducts(lipophilicnucleicacids,nucleo-bases,aminoacids,hydroxyacids,alkaloids,aminosugars),synthesisofpharmaceuticallyactivecompounds,totalsynthesisofheterocyclicnaturalproducts,andorganichydroperoxides.structureofthecatalyticspeciesisoftenknown,andstructure-activityrelationscouldbeestablished.Recentdevelopmentsofligand-freePdcatalystshaveprovidedinterestingandpracticallyimportantalternativestoligand-assistedmethodologies.Ontheotherhand,homogeneouscatalysishasanumberofdrawbacks,inparticular,thelackofreuseofthecatalystoratleasttheproblemofrecyclingofthecatalyst.Thisleadstoalossofexpensivemetalandligandsandtoimpuritiesintheproductsandtheneedtoremoveresidualmetals.1,2TheseproblemshavetobeovercomeintheapplicationofhomogeneousPd-catalyzedcouplingreactionsinindustryandarestillachallenge.3-9
YinandLiebscherInordertoaddresstheseproblems,heterogeneousPdcatalysisisapromisingoption.Here,Pdisfixedtoasolidsupport,7,10suchasactivatedcarbon(charcoal,forarecentreviewofapplicationinC-Ccouplingreactions,seeSeki,ref11a),11-13zeolitesandmolecularsieves,10,14-18metaloxides10,19-21(mainlysilicaoraluminabutalsoMgO,ZnO,TiO2,ZrO2),clays,22,23alkaliandalkalineearthsalts(CaCO103,BaSO4,BaCO3,SrCO3),porousglass,24organicpolymers,orpolymersembeddedinporousglass.25Ontheotherhand,Pdcanalsobefixedtoasolidsupportasacomplex;thatis,theligandsarecovalentlyboundtothesupport.Bothtechniquesallowonetoseparatetheheterogeneouscatalystafterthereactionortoreuseitaslongasitisnottoodeactivatedorboth.ForareviewaboutproductseparationtechniquesinHeckreactions,seeAraietal.9Alternativelysuchcatalystscanalsobeusedincontinuous-flowsystems25orinflowinjectionmicroreactors.26Normally,supportedPdcatalystsrequiremoredrasticreactionconditionsthanhomogeneouscatalysts,butthisdoesnotcauseproblemsasfarasthestabilityofthecatalystsisconcerned,becausetheyoftenarerelativelystable.Inthisway,thesomewhatloweractivitiescanbecompensatedtosomeextentbyusinghighertemperaturesandcatalystloadings.SeeDjakovitchetal.foracomparativestudyofhomogeneousversusheterogeneousPdcatalysisinHeckreactions.27Therearealsocasesreported,wherePdimmobilizedatzeolitesshowedhigheractivitythanfreePd(OAc)2or[Pd(C3H5)Cl]2,probablybecauseofthestabilizationoftheactivePdspeciesbythezeoliteframework.16ThecomparativelyhighstabilityofPdonsolidsupportssometimesallowsrunningthereactionevenundernormalambientconditions,thatis,withouttheexclusionofair.28Therewerecasesreportedwheresolid-supportedPdcatalystsshowhigheractivitiesthanhomoge-neouscatalysts,probablybecauseoftheirhigherstability.29TheapplicationofsupportedPdwasintroducedintoPd-catalyzedcouplingreactionsrelativelylate(early1970s)buthasbeenincreasinglyuseduptonow.Someindustrialapplicationshavealreadybeendeveloped.30,31
Itistheaimofthisreviewtogiveinsightintothestateofartinthefieldoftheapplicationofheterogeneouscatalystsincouplingreactionstosyntheticchemists.Scope,limita-tions,andproblemsassociatedwiththeapplicationofheterogeneouscatalystsincouplingreactionswillbecovered.TherearealsocasesincludedwherePdisfixedtoaninor-ganicsolidsupport(e.g.,silicaorironoxide)bythehelpoforganicligands,thatis,asacomplex.Suchligandscanbepartofapolymer,forexample,inglass/polymercompos-ites.32Pdcatalystssupportedbyentirelyorganicpolymersarenotincluded.10,33,34Mechanisticaspectsofthecatalysisarebrieflyaddressed,butanextensivesurveyaboutthisfieldisbeyondthescopeofthisreview.Thislimitationisalsoattributedtothefactthatthemechanismsarenotyetfullyunderstoodandfindingsinthisfieldaresometimescontra-dictory.Toanextreme,inmanycasesitisnotevenclearwhetherthegenuinecatalysisisheterogeneousorhomoge-neous.19,35Anup-to-datecriticalreviewaboutmechanisticaspectsofhomogeneousandheterogeneouscatalysisandthenatureofactivespeciesinMiziroki-HeckandSuzuki-MiyauracouplingswasrecentlypublishedbyJonesetal.36Inthepresentreview,catalystsarecoveredthatareusedassolidsandarenotsolubleinthereactionmixture,regardlessofwhethertheactingcatalyticpalladiumspeciesishomogeneousorheterogeneous.OtherrecentdevelopmentsinPdcatalysisincross-couplingreactionssuchasthe
HeterogeneousPdCatalyzedC−CCouplingReactionsChemicalReviews,2007,Vol.107,No.1135used.Ontheotherhand,caseswerereportedwherethecatalystloadingwentthroughanoptimum,thatis,higherPdloadingsdecreasedtheactivity.49Importantparametersoftheactivemetalarethesurfacearea,thedispersion(typicallyonly10-60%ofthemetalatomsareexposed),
1.1.Catalyststhesizeofthecrystallites(typicallyinarangeof2to>20Solid-supportedcatalystsarecomplexassemblies.Theirnm),thelocationintheporesofthesupport,theoxidationpreparationisachallengingtask.Minorchangesoftheirstate,thecounterionsifPd(II)isused,thewatercontent,preparationconditionscansignificantlyinfluencethedelicateandtheconditionsofitspreparation.7,50balanceofconflictingdemands:highactivity,highselectiv-Thesupportusuallyhasanimpactontheactivityofthe
ity,andlonglifetime.Palladiumcanbedepositedonasolidcatalyticsystem.Particlesize,surfacearea,porestructure,supportindifferentways.14Thepreferredmodeofdepositionandacid-basepropertiesareimportantparametersofthedependsalsoonthetypeofsupport.Withoxidesandcarbonsupport.7Thesupportcanaffectthecatalystactivityeithersupports,wetordryimpregnation,deposition-precipitation,bycreatingreactivespotsatthePdmetalcrystallites51-53ordeposition-reduction,andion-exchangemethodscanbebyimprovedreleaseofPd(0)intothesolutionbyleach-appliedusingmostoftenanaqueoussolutionofasuitableing.11,13,54Inthelattercase,thegenuinecatalyticsystemisPd(II)precursor,suchasPdCl2,Pd(NH3)4]Cl2,Pd(NO3)2,H2-homogeneous(Videinfra).Basicsupportssuchasbasic
PdCl,or[Pd(NH)](NO).Ontheotherhand,organic43432zeolites,layereddoublehydroxides,orsepiolitescanplaya乙酰丙酮solutionsofPd(0)complexes,suchasPd(acac)2(acac)similarsupportingroleasphosphinesinhomogeneousacetylacetone)orPd(C3H5)2arealsosometimesused.14Metalcatalysis49,55,56orcanactasbases,57thatis,noexternalbasesoxidesurfacesarehydroxylatedassuchorbecomehydroxy-arenecessaryinthesecases.
latedinthepresenceofaqueousPd(II)solutions.PretreatmentDuetotheircontrolledporesize,microporousandofcarboninanoxidizingenvironmentisusedtointroduce提高mesoporousmaterials,suchaszeolites,canbeadvantageousoxygen-containingsurfacegroups,thusenhancingthein-oversimplemetaloxides.Pd(0)clusterscanbeencapsulated
teractionwiththemetal.Thecatalystobtainedbytheinthesepores.Theporesizeandstructureofsuchsupportsdifferentmethodscanlateronbecalcined.ThisthermalcanhaveanimportantimpactonthereactivityandselectivitytreatmentoftenoverridesthepriorapplicationofthePdofthosecatalysts.58Thus,caseswerereportedwherealargerprecursortothesolidsupportasfarastheultimatemetalporesizeofmesoporoussilicaallowedreactionoflargerdispersionisconcerned.Ontheotherhand,thesurfaceofsubstratesascomparedwithmicroporoussupports.58thesupportcanbecovalentlyfunctionalizedbyligands,such
Pdonsolidsupportscanbeusedassuchorincombinationasphosphines,pyridines,ormercaptanes,whichform
withadditionalsolubleligands,suchasphosphines,carbenes,complexeswithdissolvedPdsalts.Thismethodologyis
andamines.Itisassumedthatsuchligandssupportleaching分离widelyusedinpolymer-46andsilica-supported47palladium
catalysts.GraftingofPdcomplexestothesolidsupportby阻止ofPd59intothesolutionactingashomogeneouscatalyst
there.Inothercases,theadditionofligands,suchasstartingwithaPdcomplexbearinglinkergroupsinthe
phosphines,inhibitsthereactionratherthanaccelerates.7,60加快ligandsisanothermethodtopreparesolid-supportedPd
Asinhomogeneouscases,heterogeneouslycatalyzedHeckcatalysts.48
reactionscanbepromotedbyammoniumsalts.61四乙氧基硅烷Sol-gelprocessescanalsobeusedforthepreparationof
Anumberofsolid-supportedPdcatalystsarecommerciallysolid-supportedPdcatalysts,mainlyforsilica-andalumina-available.However,theyoftendifferinstructure(supportsupportedPdcatalysts.Thesupportisgeneratedfroma
andPd),composition,andactivitydependingonthesupplier.monomer,suchastetraethoxysilaneoraluminumisopro-LaboratorychemicalsuppliersnormallydonotspecifythepoxideinthepresenceofasolublePdcompound,suchas
catalystmanufacturerandtheexactcatalysttype.ForPdCl2,Pd(NH3)4Cl2,orPd(acac)2(coprecipitation)and
optimizationofacatalyticsystemforlargerscaleproduction,eventuallyalinker.Inthisway,usuallyamorphousmaterials
itisnecessarytohavecontactwiththesuppliertogetalwaysareobtained,whereapartofthePdisencapsulated.Again
thesamequalityofsupportedPdortobuyastockofmaterialthesesystemscanbecalcinedlateron.
inordertoguaranteethereproducibilityofresults.WhenAlthoughtheactivespeciesinPd-catalyzedcross-coupling
syntheticchemistswanttoapplymethodsreportedinthereactionsisPd(0),themetalcangenerallybeusedasPd(0)
literatureforheterogeneouscatalysis,theyshouldbesureorPd(II)28onthesolidsupport.Inthelattercase,insitu
togetthesameorsimilarcatalystasreportedinthereductiontoPd(0)occursduringtheapplicationincross-procedure.Differencesfromtheoriginallyusedsystemcancouplingreactionswithouttheadditionofextrareducing
causeunwantedeffects.reagents,thatis,anamine,aphospineusedasligand,ora
ThecharacterizationofaheterogeneousPdcatalystonareactantreducesthePd(II)species.Inthecaseofcarbon-molecularlevelisstillaproblem,althoughTEM,X-raysupportedPd,partofthePd(II)isalreadyreducedtoPd(0)
起作用diffractometry,andIRspectroscopyallowimportantinsightsduringthepreparationofthecatalyst.Ontheotherside,
intothestructure.Often,heterogeneouscatalystsarestilltransformationofPd(II)intoPd(0)canbeimplementedby
chosenonanempiricalbasiswithoutunderstandingwhyaanextrareductionstep,forexample,byhydrazine,formal-givencatalystissuperiortoanotherone.dehyde,orhydrogen,oroccursalreadyinitspreparation,
whenthedeposition-reductionmethodologyisused.Gas-Reusageofaheterogeneouscatalystisoftenpossiblebut
phasereductionleadstosmallerPdparticlesthanliquid-issometimeslimitedduetoleachingofthePdwithout再沉淀14phasereduction.GenerationofthePd(0)fromPd(II)atredeposition(leachingupto14%PdfromPd/Cwasobserved
inHeckreactions62),changingofcrystallitestructureofthethesolidsupportcanoftenbeadvantageousbecausespecies
Pdonthesupportsurface,28,50chemicalchangeofPdligandsaregenerated,whichexhibitahighercatalyticactivity.
(e.g.,oxidationofphosphanesleadingtohighleachingofAloadingwith5wt%PdisusedformostofthePd
Pd)graftedtothesolidsupport,orcongestingthecatalystcatalysts;however,forspecialpurposeshigherloadingsare
applicationofcolloidalPd,37,38Pdclusters,39Pdblack,40
andPdnanoparticles41-45arenotconsideredinthisreviewbutwillbeoccasionallymentionedwhentheheterogeneouscatalystservesasasourceforsuchPdspecies.
136ChemicalReviews,2007,Vol.107,No.1surface,forexample,bysaltsformedasbyproductsinthecouplingreaction.58Therewerecasesreportedwherethecatalyticactivitydroppedconsiderablyinthesecondrun,whilemarginallossesofcatalyticactivitywereobservedinthefollowingruns.58ReuseofcatalyticPdcanalsobeachieved,whencolloidalPdisformedbyleachingfromthesupportandthesecolloidalparticlesareseparatedandsubmittedtoanotherrun.38Interestingly,thereareafewcasesreportedwheretherecycledcatalystexhibitedhigheractivitythantheoriginalone.52
Palladiummetalwithoutasolidsupporthasrarelybeenusedincross-couplingreactions.40,63,64Palladiumoncharcoal(alsocalledactivatedcarbon)(Pd/C)isbyfarthemostoftenusedcatalystinheterogeneousPd-catalyzedcouplingreac-tions.Itcanbepurchasedfromvariouslaboratorysuppliers,suchasAcros,Aldrich,Lancaster,orAlfaAesar,orfromthemanufacturersDegussaorJohnsonMattheyinvariousqualitieswithaPdcontentrangingfrom1%to20%.Thematerialscancontainwaterupto50%.Pd/Cisusedwithorwithoutadditionalligands.ProceduresforthepreparationofPd/Cwerereported.14,65
Cross-couplingscatalyzedbysolid-supportedPdcanbecarriedoutinorganicsolvents.Organicsolvent/watermixtureswerealsoused,andafewcaseswerereportedusingionicliquids12,66-69orworkingundersolvent-freeconditions.
1.2.MechanisticAspectsIngeneral,carbon-carboncouplingreactionscatalyzedbysolid-supportedPdfollowtheusualreactionmechanism,asshownforcouplingoforganometallicswithorganohalidesor-triflatesinScheme1.70-72
Scheme1.MajorStepsofPd-CatalyzedCouplingReactions
RecentresultsfromAmatoreandJutantgaveevidenceforananionicversionofthecatalyticcycleinHeckandotherPd-catalyzedcouplingreactionsunderhomogeneouscondi-
YinandLiebschertions(Scheme1b).72ProbablythismechanismismoreabundantthanthetextbookcycleshowninScheme1aunlessaryltriflatesorareneswithnon-halideleavinggroupsareused.36InvolvementofPd(IV)speciesasintermediateswastakenintoconsideration73butseemstobeunlikelyinlightoflaterresults.36,74,75Eachofthestepsofthecatalyticcyclescanberate-determining,dependingonthetypeofsubstrateandcatalyst.
AsfarastheinteractionofthePdcatalystwiththesubstrateandintermediatesisconcerned,severalmechanismshavetobetakenintoconsideration.36ThusthereactioncantakeplaceatthesurfaceofsolidPd51,76asatrulyheteroge-neousreaction.Ontheotherside,aquasi-homogeneousmechanismcanoccur,wherePdgetsdissolvedascol-loids42,74,77orascomplexesthathavebeenleachedfromthesupportedPd,forexample,byoxidativeadditiontothesubstrate.10,11,13,19,21,28,38,48,50,74,78,79Despiteearlierreportsgiv-ingsomeevidence(hotfiltrationtest,Hg(0)poisoning,...)for,butnotproving,80aheterogeneousmechanism,ithasbecomemoreandmoreacceptedthatleachedsolublePdspeciesarethegenuinecatalyticallyactivespeciesinHeckandalsoinmostothercouplingreactionsimplementedbysolid-supportedPd.36,74ThephenomenonthathomeopathicdosesofdissolvedPdcancatalyzecross-couplingreactionsmakesitdifficulttofindoutthetruenatureoftheactingcatalyticspecies.74,81TherewerecasesreportedwherethedissolvedPdformedbyleachingcatalyzestheHeckreaction,whereassolidPdparticlesgiverisetosidereactionssuchasdehalogenationreductivecouplingofhaloarenes.27,82Ingeneral,leachingissupportedbypolarsolvents,suchasDMForN,N-dimethylacetamide.49,83,84TheoxidationstateofthePdonthesolidsupportcanalsohaveaneffectontheextentofleaching(Pd(II)ispronetoleaching).61,84Inthecaseofaheterogeneousmechanism,thesupportcanaffectthestructureofthePdcreatingreactivespots(edges,corners,adatoms)ofhighcatalyticactivityinthecrystallitestructureorcanprovidereactioncavities,forexample,incaseofPdsupportedbyzeolites.Ontheotherhand,activationofthePdsurfacebythesupportcanalsoprovidebetterdesorptionleadingtofasterformationofcolloidsorcomplexesinsolution,theheterogeneousPdthusservingasareservoirfordissolvedspecies.AsfoundinHeckreactionscatalyzedbyPd/C,Pd/alumina,Pdonzeolites,orPdonsilicoalumi-nophosphates,Pdcandissolveinthebeginningofthereaction,whilereactantsprobablyactasligandsfortheformationofcomplexes.11,19,28,35,38,82,84-86TheconcentrationofPdinsolutionwasfoundtobehighestatthebeginningofthereaction(20%ofthetotalcontentofPd)andgraduallydroppedwiththeprogressofthereaction.Asthereactioncomestoanend,mostofthePdreprecipitatedatthecarbonduetothelackof“reactantligands”.Properlyestablishedreactionconditions(increasedreactiontemperature,additionofreducingagents,andworkingunderinertconditions)allowedthentheminimizationofthefinalPdconcentrationinsolution.28,38,87Sometimesthefinalconcentrationcouldbereducedtolessthan1ppm.28
ChangesofthecrystallitestructureofthestartingPd/CascomparedwiththefinalPd/Cwereobservedinsuchcases.28EffectiveretrappingoftheregeneratedPd(0)speciesformedinthereductiveeliminationbythesolidsupport(e.g.,charcoal)isapreconditionforreusablecatalysts.11,38,88Sometimesre-depositionofleachedPdcanbesofastandcomprehensivethatitcanmasktheleachingphenomenon.ThedepositionofdissolvedPdspeciescanoccurnotonly
HeterogeneousPdCatalyzedC−CCouplingReactionstotheoriginalsupport(re-deposition)butalsotoothersupportsaddedtothemixture,orthedissolvedspeciescanprecipitateasfreePdparticles.38Naturallythere-depositedPdexhibitsdifferentpropertiesduetocrystallitegrowthascomparedwiththestartingPdsystem,andthusnormallythecatalyticactivitydropsaftereachrunwhenthematerialisusedseveraltimes.28,50Asanothereffect,re-depositedPdcancatalyzeunwantedsidereactions,whileonlythedis-solvedPdsupportstheenvisagedcross-coupling.11,28
2.SuzukiReactions2.1.PdonCarbon(Pd/C)TheSuzuki-Miyaurareactionhasbecomeamainstayofmodernsyntheticorganicchemistryforthepreparationofbiarylcompounds.89-91Inthepastdecade,thePd/C-catalyzedarylationbySuzuki-Miyaurareactionhasbeenappliedwidelyinorganicsynthesisofbiarylcompounds,whichcanalsobeheterocyclic.Itcanfurtherbeusedincouplingofvariousorganicmoietiesdifferentfromarylcompounds,suchasalkenes,alkynes,oralkanes.ThefirstexampleofPd/C-catalyzedSuzukireactionwasreportedbyMarckandco-workersin1994.92Ingeneral,Pd/Cisusedwithorwithoutadditionalphosphineligands,andoftentheapplicationofaqueoussolventsisadvantageous.
2.1.1.InthePresenceofPhosphineLigandsInthefirstexamplesoftheapplicationofPd/CinSuzuki-Miyauracouplings(Scheme2),triphenylphosphinewasusedasaligandadoptingthemethodologyfromhomogeneouscatalysis.3Thebromoarene1andthetriflate3weretransformedintothecorrespondingdiarylproducts2and4inhighyields.92
Scheme2.Pd/C-CatalyzedSuzukiCouplinginthePresenceofPPh3
Nishidaandco-workers59foundthataphosphineligandwasindispensableforthePd/C-catalyzedSuzukireactionsofhalopyridinesandhaloquinolinesinmostcases(Table1).Thereactionsofbromopyridines5a-c,2-chloropyridine(5g),2-chloropyridineswithanelectron-withdrawinggroup5d-f,5h,and5i,andhaloquinoline7aand7bproceededsmoothlyandgavetheproductsingoodyields(Table1,entries1-9,14,15,and17).However,thereactionsof2-chloropyridineswithanelectron-donatinggroup,5jand5k,gaveunsatisfactoryresults(Table1,entries10and11).Thereactivityofthesubstrateshowedthesametendencyaswasseeninthereactionwithahomogeneouscatalyst;thatis,chloropyridineswithanelectron-withdrawinggroupweremorereactivethanthosewithanelectron-donatinggroup.Inordertoimprovetheyieldsofless-reactivesubstratessuchas3-chloropyridine(5l),4-chloropyridine(5m),and6-chloroquinoline(7c),ligandeffectswerestudiedbyusing
ChemicalReviews,2007,Vol.107,No.1137Table1.Pd/C-CatalyzedSuzukiCouplingofN-Heterocycles5,7,or8withPPh3
entryhaloheterocycleligandyielda(%)15a:R)H,X)2-BrPPh38525b:R)H,X)3-BrPPh39035c:R)H,X)4-Brb
PPh36045d:R)3-NO2,X)2-ClPPh39455e:R)5-CN,X)2-ClPPh39065f:R)5-NO2,X)2-ClPPh38575g:R)H,X)2-Clnone0PPh38285h:R)3-CN,X)2-Clnone16PPh310095i:R)5-CF3,X)2-Clnone30PPh385105j:R)6-OMe,X)2-ClPPh325115k:R)3-NH2,X)2-ClPPh319125l:R)H,X)3-ClPPh32135m:R)H,X)4-ClbPPh39147a:X)2-Clnone0PPh391157b:X)3-Brnone0PPh391167c:X)6-ClPPh3017
8
none36PPh3
72
a
Isolatedyield.bPyridiniumhydrochloridewasused.
3-chloropyridine(5l)andPd/C.Thestericallyhindered2-(dicyclohexylphosphino)biphenyl12(9mol%)wasfoundtoimprovetheyielddramatically(Table2,compareentries1and3).59,93Ithasbeenreportedthatbulkyandelectron-richligandsincreasetheyieldsofhomogeneousSuzuki-Miyauraandothercouplingreactions.91Theseligandsfacilitateoxidativeaddition,andthespatialbulkaroundthemetalpromotesreductiveelimination.Thus,duringthePd/C-catalyzedreaction,12wouldinteractwiththeleachingPdandshowthesameeffects.ThecombinationofPd/Cand12wasalsoeffectiveforthereactionsof4-chloropyridine5mand6-chloroquinoline7c(Table2,entries4and5).59Remarkably,thiscombinationwasnoteffectiveinthereactionof4-methoxychlorobenzene11,butPd(II)/Cand12providedhighyieldsoftheproduct.(Table2,entry6).
Table2.Pd/C-CatalyzedSuzukiCouplingofN-Heterocycles5,7c,or4-Methoxychlorobenzene,11,withDifferentLigands
entryhaloheterocycleligandyielda(%)15l:R)H,X)3-Cldppp025l:R)H,X)3-Cldppb035l:R)H,X)3-Cl128845m:R)H,X)4-Cl129257c:X)6-Cl12776
11
12
80b
a
Isolatedyield.bPd(II)/Cwasused.
138ChemicalReviews,2007,Vol.107,No.12.1.2.IntheAbsenceofPhosphineLigandsAlreadyintheearlyinvestigationsoftheapplicationofPd/CinSuzuki-Miyauracouplings,itwasfoundthatligand-freemethodologycanbeadvantageous.92Goodtoexcellentyieldsofcouplingproductswereobtainedwhenbromide,iodide,ortriflateactedasleavinggroup(Table3).Chlorosubstituentsinthearylboronicacidweretolerated;thatis,theydonotreactintheSuzukicoupling.TheresultsgaveevidencethatthePd/C-assistedcouplingreactionsmightoccurbyheterogeneouscatalysisundertheseconditions.
Table3.Ligand-FreePd/C-CatalyzedSuzukiCoupling
yieldaAr,XAr′baset(h)(%)4-CHO-Ph,Br4-F-Ph
Et3N5844-CN-Ph,Br4-Cl-3-F-PhNa2CO31943,5-(CF3)2-Ph,Br4-n-Pr-PhNa2CO3
0.5904-n-Pr-Ph,Br3,5-di-F-Ph2MNa2CO319883-F-4-OH-Ph,Br4-n-Pen-PhNa2CO31980b4-Me2N-Ph,Br4-Cl-3-F-PhNa2CO31995Ph,I4-Cl-3-F-PhNa2CO319914-Cl-3-F-PhNa2CO319944-Et-Ph,Br4-Cl-3-F-Ph2MNa2CO31987b4-CN-Ph,OTf
PhNa2CO31950Ph
Na2CO3
18
84c
a
Isolatedyields.bDMEassolvent.cDMFassolvent.
In2001,LeBlondandco-workers76foundanefficient
methodologytocoupleweaklyreactivearylchlorides,whichhadbeenaprobleminhomogeneousSuzukicouplingforalongtime.Pd/CinDMA/waterwasappropriate.TheoptimalvolumetricratioofDMA/waterwasfoundtobe20:1,enablingthecross-couplingtogotocompletionwithin1.5hwithouttheformationofhomocouplingproductsfromthearylchlorides.Theseconditionsaregenerallyapplicabletowardarylchlorideswithelectron-withdrawinggroupsandgave79-95%yields(Table4).Moderateyieldswereobtainedwithneutralorelectron-richarylchlorides,whichcouldbeimprovedbyusinggreateramountsofcatalyst(seeentry7).
Table4.Pd/C-CatalyzedSuzukiCouplingofArylChlorides
entryRR′yielda(%)conv(%)1NO2H931002CF3H951003CNH831004AcH791005HOMe45616OMeH32
37
7
Me
H
36,b54c
65,b76c
a
Isolatedyield.b48h.c15mol%ofPd/C.
DetailedinvestigationsbyKo¨hler’sgrouponSuzukireactionsofarylbromidesandchlorideswithphenylboronicacidgaveimportantinsightsintheeffectoftheconcentrationofthePd/Ccatalystandotherreactionconditionsonthecatalyticactivity,theyield,andtheselectivity.81Underoptimizedconditions,couplingproductsofbromoarenesand
YinandLiebscherphenylboronicacidwereobtainedinexcellentyieldsaftershortreactiontimesbyusingextremelylowPdconcentra-tionsofonly0.005-0.01mol%(Table5,entries1-4).HighTON,upto20000,wereachieved.Alsodeactivatedbro-moareneslikep-bromoanisolecouldbeconvertedupto83%withoutdehalogenationwithin60min(Table5,entry5).ThehighestTOFwas16600h-1,and100%selectivityfortheSuzukicouplingproduct(cross-coupling)wasfoundnearlywithoutexceptions.p-ChloroacetophenonecouldbeconvertedquantitativelyatPdconcentrationsof0.25mol%within4h.Conversionsupto90%wereachievedafter2husing0.005-0.10mol%Pd.
Table5.Pd/C-CatalyzedSuzukiCouplingofArylHalideswithPhenylboronicAcid
entryXR(molPd/C%)NMP/H2Obase(h)tconv(%)yield
(%)TONTOF
1BrCN0.0110:4Na2CO31.51001001000066662BrH0.00510:4Na2CO3210010020000100003BrOH0.0110:4Na2CO321001001000050004BrOMe0.00510:4Na2CO3210010020000100005BrOMe0.00510:4Na2CO31838316600166006ClAc0.2510:3NaOH4100984001007ClAc0.1010:3NaOH290889004508
Cl
Ac
0.05
10:3
NaOH
2
80
78
1600800
Theadditionofwatertotheorganicsolventincreasedtheactivity.Acrucialinfluencewasfoundforthebase.Na2-CO3gavethebestresultsforcouplingsofarylbromides,whereasNaOHpromotedthedeborylationanddehalogena-tionresultinginadecreasedselectivity.Incontrast,NaOHisfoundtobethebestchoiceforactivatedarylchloridesundertheconditionsapplied(120°C,NMP/water).Againithastobementionedthattheoptimumreactiontemperature(120°C)ishigherthaninatypicalhomogeneouslycatalyzedSuzukireaction(about80°C).
Ontheotherhand,roomtemperaturewasappropriateinPd/C-catalyzedcouplingofiodophenols17witharylboronicacidsinwaterinthepresenceofK2CO3(Table6).88Inthecaseofbromophenol,highertemperaturewasadvantageous(entries8and9).
Table6.Pd/C-CatalyzedCouplingofHalophenolswithArylboronicAcidinAqueousMedia
entryhalophenolarylboronicacidT(°C)yield(%)12-iodophenolPhB(OH)2RT7023-iodophenolPhB(OH)2RT9734-iodophenolPhB(OH)2
RT>9944-iodophenol4-FC6H4B(OH)2
RT>9954-iodophenol4-MeOC6H4B(OH)2RT>9964-iodophenol4-MeC6H4B(OH)2RT>9974-iodophenol2-MeOC6H4B(OH)2RT9884-bromophenolPhB(OH)2RT359
4-bromophenol
PhB(OH)2
50
76
ItisnoteworthythattherecoveredPd/Cpossessesenoughcatalyticactivityforfurthercouplingreactions.ApplicationofrecoveredPd/Ctothecouplingof4-iodophenolandphenylboronicacidrevealedthatthecatalyticactivitygradu-
HeterogeneousPdCatalyzedC−CCouplingReactionsallydiminished,buttheyieldwasstill89%afterthefifthreuse(Table7).
Table7.Reactionof4-IodophenolwithPhenylboronicAcidUsingRecoveredPd/CasCatalyst
entryPd/Ccatalystyield(%)1fresh>992firstreuse953secondreuse944thirdreuse905fourthreuse896
fifthreuse
89
Recently,Sajikietal.reportedanefficientprotocol94forthephosphine-freeSuzukireactioncatalyzedbyPd/Catroomtemperature.UnlikeintheprocedureusedbyKo¨hleretal.81(Videsupra),acommercialcatalystwasused,andthereactioncouldbecarriedoutatroomtemperatureomittingtheneedforsealedtubesbutneedingmuchhigherquantitiesofcatalyst(10mol%).Bromoareneswitheitherelectron-withdrawingsubstituents,suchasNO2,CHO,COCH3,orCO2C2H5,orelectron-donatingsubstituents,suchasOCH3,coupledreadilywitharylboronicacidsinexcellentyields(Table8)usingcommerciallyavailable10%Pd/C(3.5mol%)inethanol-H2O(1:1)andNa2CO3.Arylbromidescontainingelectron-withdrawingsubstituentsreactedfasterthanthosewithelectron-donatingsubstituents(forexample,entry1vsentries2-4).
Table8.Pd/C-CatalyzedSuzukiCouplingofArylBromidesandArylboronicAcidsatRT
entryRR′t(h)yielda(%)1OMeH6952AcH5993NO2H2>994CHOH
5>995Ac4-OMe2976CHO4-OMe2967NO24-OMe1988OMe4-OMe5>999Ac3-OMe3>9910OMe2-OMe59411NO22-OMe4>9912CHO2-OMe59813Ac2-OMe4>9914NO24-Ac19>9915
CO2Et
H
3
99
a
Isolatedyield.
Thecatalystcouldberecoveredusingasimplefiltrationandwashingsequence.Reusewaspossiblewithoutsignifi-cantdecreaseincouplingyieldeveninthefourthrun.Ligand-freePd/C-catalyzedSuzuki-Miyauracouplingalsotoleratesacidgroupsinthehaloareneandinthearylboronicacid.Itwasusedinthesynthesisofbiarylaceticacids21(Scheme3).95
Scheme3.SynthesisofBiarylaceticAcidsbyPd/C-CatalyzedArylation
ChemicalReviews,2007,Vol.107,No.1139ThePd/C-mediatedsynthesisofthediarylcarboxylicacid24wasimplementedonalargescale(2×6.3kgbatches)inapilotplant(Scheme4).31Similarly,aphenyldiboronatewascoupledtwicewith3-iodophthalateunderligand-freeconditionsinthepresenceofCs2CO3.96
Scheme4.Multikilogram-ScaleSynthesisofSB-251475
TheintegrityoftheconfigurationwasmaintainedinthePd/C-catalyzedSuzukicouplingofopticallyactive4-bro-momandelicacidsinthepresenceofNa2CO3providingenantiopure4-arylmandelicacids26(Scheme5).97Both,electron-donatingandelectron-withdrawinggroupsweretoleratedinthearylboronicacid.
Scheme5.CouplingofOpticallyActive4-BromomandelicAcidwithArylboronicAcids
Recently,itwasshownthattetraarylboratescanbeusedinligand-freePd/C-catalyzedSuzukireactionofbromo-arenes.98Variousbiarylcarboxylicacidsandphenolswerepreparedinhighyields(Table9).Again,thecatalystcouldbereusedseveraltimes.Forexample,couplingof4-bro-mobenzoicacidwithsodiumtetraphenylboratecatalyzedbyrecoveredPd/Cprovided88%,84%,81%,and76%yieldinthefirsttothefourthreuse,respectively.
Bromo-andiodoheteroarenescanalsobeusedinligand-freePd/C-catalyzedSuzukicoupling.Thusthequinoline30wasobtainedwithaverylowlevelofresidualPd.LeachedPdwasfoundinthereactionmixture,whichdiminishedtolessthan4ppmaftercompletionofthereaction;thatis,thereactionrunsbyhomogeneouscatalysis(Scheme6).87
ThePd/C-catalyzedsynthesisofpyrazolylphenylsulfon-amides32wasimplementedin100-mgscaleusingaQuestmodel210synthesizer(Scheme7).99
5-Aryl-2-furfurals34weresynthesizedbyPd/Ccatalyzed,ligand-freeSuzukicouplingstartingfromthecorrespondingdiethylacetal33(Table10).100
AstrongeffectofthehalidewasfoundinPd/C-catalyzedligand-freeSuzukicross-couplingof2-halocycloalkenoneswitharylboronicacids.101While2-iodocycloalkenones35reactedundermildconditionsat25°CunderairinaqueousDME(Table11),thecorresponding2-bromo-2-cyclohexen-1-onecompletelyfailedtoundergoSuzukicouplingunderthesameconditions.Onlyextensivedecompositionofstartingmaterialswasobserved.101
Thecouplingof2-iodo-2-cyclohexen-1-onewithphenyl-boronicacidwasalsoexaminedusingrecoveredcatalyst.ItwasfoundthatthePd/Ccatalystcouldbereusedatleastfiverunswithoutaffectingtheyield(79-85%).Theprogres-sivedecreaseintheactivitycouldbeefficientlybalancedbyincreasingthetemperatureofthereactionfrom25to50°C.101
140ChemicalReviews,2007,Vol.107,No.1Table9.Pd/C-CatalyzedSuzukiReactionsofArylBromideswithSodiumTetraphenylborate
a
Reactionconditions:0.27equiv(basedonbromide)Ph4BNa,2.00equivNa2CO3,refluxunderairfor1h.bYieldsdeterminedbyHPLCanalysis.cReactiontimewas24h.
Scheme6.Pd/C-CatalyzedSynthesisofArylquinoline30
Scheme7.Pd/C-CatalyzedSynthesisofPyrazolylphenylsulfonamides32
2.1.3.SurfactantsLigand-FreeSuzukiCouplinginAqueousAlthoughmanyPd/C-catalyzedSuzukireactionsprovidedgoodresultsinwaterorwater/organicsolventmixtures,itcanbeusefultousewaterinthepresenceofsurfactants,
YinandLiebscherTable10.Pd/C-CatalyzedOne-PotSynthesisof5-Aryl-2-furfurals
Art(h)yielda(%)4-NO2-Ph2813-NO2-Ph2912-NO2-Ph16844-MeO2C-Ph18784-CF3-Ph6912-thienyl
36
79b
a
Isolatedyield.bAdditionalPd/C(10wt%)wasrequired.
suchastetrabutylammoniumbromide.Themethodologycanprovidethefollowingadvantagesincomparisonwithmoreconventionalprocedures:noorganicsolventisneeded;ultralowsurfacetensionallowsfastandeasymixingofreagents;thesystemsareformedspontaneouslyandvigorousmechanicalorultrasonicagitationisnotneededtoobtainandmaintainthesesystems.
Arcadietal.reportedamildandversatilemethodforPd/C-catalyzedSuzukicouplingofarylhalidesinwaterandsurfactants.102Theconcentrationofthesurfactantsinwaterplayedapivotalrolefortheoutcomeofthereaction.Aseriesofbiarylswereobtainedingoodtoexcellentyieldsfromaryliodides,bromides,andchlorides(Table12,exceptionof4-chloroanisoleinentry12).
Theexperimentalprocedureisverysimple.Liquid-liquidextractionwithacommonorganicsolvent,suchasdiethylether,allowsthequantitativerecoveryoftheproductfromthewater-surfactantPd/Csystem.Theactivityoftherecoveredwater-surfactantPd/Csystemwasmonitoredusingthereactionof4-bromoanisolewithPhB(OH)2.Althoughthecatalyticactivitygraduallydiminished(yieldof4-methoxybiphenylforfirstreuse95%,secondreuse88%,thirdreuse85%,andfourthreuse80%),theyieldwasstill80%evenafterthefourthreuse.
Amarkedeffectoftetrabutylammoniumbromide(TBAB)ontheyieldofproducts39wasfoundinthePd/C-catalyzedSuzukireactionofchloro-andbromopyridines38withphenylboronicacidinwater.59Theyieldsincreasedfrom21-55%to67-95%whenTBABwasused(Table13).In2005,Ko¨hler’sgroupdevelopedligandlessPd/C-catalyzedSuzukicross-couplingreactionsofvariousarylchloridesinaqueoussurfactant(TBAB).Thisprocedureisaveryattractivewayofaccessingmultifunctionalbiarylsbecausesensitivefunctionalgroupslikeesterandnitrilegroupsaretolerated(Table14).103
2.1.4.UltrasoundLigand-FreeConditionsSuzukiCouplingunderMicrowaveorMicrowave(MW)heatingandhigh-intensityultrasound(US)haveemergedaspowerfultechniquesbywhichreactionscanbebroughttocompletioninshorterreactiontimesinanumberofcases.SuchconditionscanalsobeadvantageousinPd/C-catalyzedSuzukicross-couplingreac-tions.
Leadbeateretal.reportedthePd/C-catalyzedSuzukicouplingofarylchlorideswithphenylboronicacidinwaterusingmicrowaveheatingwithsimultaneouscooling(Table15).104
HeterogeneousPdCatalyzedC−CCouplingReactionsTable11.Pd/C-CatalyzedSuzukiCouplingof2-IodocycloalkenoneswithArylboronicAcids101
a
Isolatedyields.
Pd/C-catalyzedcouplingofiodoareneswithmethoxyphen-ylboronicacidsinmethanol/waterusingKFasthebasegavehighyieldsofthediaryl42underultrasoundirradiation(Scheme8).70
Inthebromo-andiodoareneseries,thesimultaneoususeofhigh-intensityultrasoundandmicrowaveirradiation
ChemicalReviews,2007,Vol.107,No.1141Table12.Pd/C-CatalyzedSuzukiCouplingofArylHalideswithArylboronicAcidsin0.1MaqCTAB
entryAr1
XAr2T(°C)t(h)yield(%)14-MeO-PhIPhRT249524-MeO-PhBrPh
RT249434-MeO-PhBr4-Me-PhRT249644-MeO-PhBr4-FRT248954-MeO-PhBr3-OMeRT246565-pyrimidylBrPhRT246574-CHO-PhBrPhRT247482-NO2-PhBrPh60249592-Ac-PhBrPh60489104-Ac-Ph
ClPh1002485112-NH2-4-CF3-PhClPh100249612
4-MeO-Ph
Cl
Ph
100
24
6
Table13.Pd/C-CatalyzedSuzukiCouplingofPyridylHalidesinAqueousTBAB
TBAByieldapyridylhalide(equiv)(%)R)H,X)2-Br0210.167R)H,X)3-Br0540.185R)H,X)4-Brb0550.3671.595R)3-NO2,X)2-Cl0490.1670.387R)5-CN,X)2-Cl
0341.5
69
a
Isolatedyields.bPyridiniumhydrochloridewasused.
Table14.SuzukiCross-CouplingofArylChloridesinaqTBAB
base,PhB(OH)2T(°C),yieldaRPd(%)equiv(equiv)t(h)(%)4-Ac0.2NaOH,2.51.1100,2994-CN0.5KF,2.51.1100,3982-CN0.5KF,2.51.1140,3894-CO2Me0.5KF,2.51.1140,387H0.5KF,2.51.1140,673b4-Me2NaOH,51.5140,6812-Me2NaOH,51.5140,6744-OMe2NaOH,51.5140,6834-NH2
2
NaOH,5
1.5
140,6
66c
a
Isolatedyield;reactionconditions,4mmolofArClin6mLofwater.b4-Tolylboronicacidwasused.cDeterminedby1HNMR.
sometimesgavebetterresultsinligand-freePd/C-catalyzedSuzukicross-couplingreactionsthanjustusingoneoftheseeffects(Table16).105
2.2.PalladiumonMetalOxides2.2.1.Palladium-DopedKF/Al2O3Palladium-dopedKF/Al2O3wasusedinsolvent-freeSu-zukicouplings.Aseriesofbases,organohalides44,andboronicacids45wereinvestigated.106KFturnedouttobe
142ChemicalReviews,2007,Vol.107,No.1Table15.CouplingofArylChlorideswithPhenylboronicAcidunderMicrowaveIrradiationa
arylchloride
reactionsimultaneous(R)time(min)
cooling
yield(%)4-Ac10no89yes904-NO210no96yes944-CN10no79yes804-Me10no40yes752-Me10no25yes64H10no59yes654-OMe10no36yes652-NH2
30
no21yes
56
a
Reactionswereruninasealedtubeusing1mmolofarylchloride,1.3mmolofphenylboronicacid,1mol%Pd/C,3.7mmolofNa2CO3,1mmolofTBAB,and2mLofH2O.Aninitialmicrowaveirradiationof300Wwasused,thetemperaturebeingrampedfromroomtemperatureto120°C.
Scheme8.Ultrasound-PromotedSuzukiCouplingofIodobenzeneand4-MethoxyphenylboronicAcid
Table16.SuzukiCouplingofArylHalideswithPhenylboronicAcida
USbMWcUS/MWdarylhalideyield(%)yield(%)yield(%)
4-iodoaniline90864-bromoaniline97904-iodoanisole72783-bromoanisole5464882-bromoanisole79702-iodothiophene403759
1-iodonaphthalene32634-bromobenzonitrile
78
74
a
Underargonatmosphere,1mmolofphenylboronicwasreactedwith1mmolofarylhalideand2mmolofK2CO3,using0.05mmolofPd/Cascatalyst.bUltrasoundirradiation(20.5kHz,90min),THF/waterorDME/water,1:1,assolventat45°C.cMWirradiation(700W,20min),DMEassolvent.dDME/water,2:1,assolvent,1hirradiation(US20.5kHz,MW700W).
themosteffectivebase.Asusual,aryliodidesgavebetterresultsthanthebromidesandchlorides(Table17).Aryl-boronicacidsaremorereactivethanalkenylboronicacidsandalkylboronicacids.RelativelyhighquantitiesofPdwereused.
Solvent-freeSuzukireactionscatalyzedbyPd-dopedKF/Al2O3werealsoinvestigatedundermicrowaveirradia-tion.107,108Reductionofreactiontimesfromhourstoafewminutescouldbeachievedinthisway(Table18).Again,relativelyhighamountsofPdwerenecessary.Thecatalystcouldberecoveredbyasimplefiltrationandwashing
YinandLiebscherTable17.SuzukiReactionsCatalyzedbyPdDopedonKF/Al2O3
a
Isolatedyields.
sequenceandcouldbereused.Suzuki-Miyauracouplingofiodobenzenewithtolylboronicacidundersolvent-freeconditionsapplyingthermalandmicrowaveenhancementrevealedthattherecoveredcatalystexhibitedthesameactivitythroughatleastsixcycles.107
Table18.MW-EnhancedSolvent-FreeSuzukiReactionsonPd-DopedKF/Al2O3
Ar-XAr′conditionsyield(%)refPh-I4-Me-Ph15min,30W98108Ph-I
4-MeO-Ph2min,90W951084-Me-Ph-IPh
2min,90W82108Ph-I3-Cl-Ph2min,60W581082-Py-BrPh5min,60W661082-Py-BrPh
5min,60W40108Ph-I4-Me-Ph2min,100W82107Ph-Br4-Me-Ph2min,100W52107Ph-Cl4-Me-Ph2min,100W4107Ph-I
4-Cl-Ph
2min,100W
87
107
2.2.2.Pd−N-HeterocyclicIronOxideNanoparticle-SupportedCarbeneComplexesAkindofPd-N-heterocycliccarbenecomplex(Pd-NHCcomplex)fixedtoironoxideviaapolymerwaspreparedbyGao’sgroupasshowninScheme9.ThecatalystwasstableanddemonstratedhighcatalyticactivityinpromotingSuzukireactions.109Highyieldswereachievedwithvariousaryliodidesorbromidesandarylboronicacidsusingonly0.015mol%catalyst(Table19).
Scheme9.PreparationofFe2O3Nanoparticle-SupportedPd-NHCComplex
HeterogeneousPdCatalyzedC−CCouplingReactionsTable19.SuzukiCouplingsofArylHalidesandArylboronicAcidsCatalyzedbyFe2O3-Nanoparticle-SupportedPd-NHCComplex
R1XR2yielda(%)
HI2-Me86HI3-Me88HI2-OMe84HI3-Ac89HI1-Naph82HI4-CN822-MeIH874-MeIH882-OMeIH744-OMeIH834-AcIH803-MeBrH742-OMeBrH703-OMeBrH724-OMe
Br
H
78
a
Isolatedyields;averageofatleasttworuns.
Asaspecialfeature,therecoveryofthisparamagneticcatalystwasfacilelyachievedbyusingapermanentmagnet.Isolatedcatalystswereusedforsubsequentnewroundsofreactionswithoutsignificantlossofcatalyticactivity.
Later,Gao’sgrouppreparedanotherkindofmagneticmaghemite(γ-Fe2O3)-silicananoparticleswherePdwascomplexedviaatetherednitrogenheterocyclicApplicationcarbene(Fe2O3-Si-Pdcatalyst)(Figure1).ofthiscatalystinSuzukicouplingreactionsofaryliodidesorarylbromidesgavegoodresults(Table20).110
Figure1.Structureofmaghemite-silicananoparticle-supportedNHCPdcomplex.
Table20.Maghemite-Silica-Nanoparticle-SupportedPd-CatalyzedSuzukiReactions
GCisolatedRXyield(%)yield(%)2-MeI95a872-MeBr93842-OMeI99914-Ac
I
99
93
a
Firstrun;thesecondtofifthroundyieldgave94%,95%,93%,and93%yield,respectively.
2.2.3.Palladium-ContainingPerovskitesItwasdemonstratedthatPd-containingperovskitesareageneralclassofheterogeneouscatalystspossessingutilityincross-couplingreactions.111Themechanisminvolvesthegenerationofsoluble,catalyticallyactivepalladiumspeciesthathavebeendesorbedfromthebulkinorganicphaseandwillprobablybere-depositedonamodifiedsolidphaseafterthereactioniscomplete.Palladium-containingperovskites
ChemicalReviews,2007,Vol.107,No.1143alsoturnedouttobeeffectivecatalystsinSuzukicouplingreactionsofaryliodidesandarylbromides.112Thecatalystcouldeasilyberecoveredandreused.113Inthecaseofcouplingof4-bromoanisoleandphenylboronicacid,thecatalystcouldbeusedforfiverunswithoutanydedectablelossofcatalyticactivity(Scheme10).
Scheme10.RecoveredPd-Perovskites-CatalyzedSuzukiCoupling
2.2.4.MiscellaneousMetalOxidesRecently,Helletal.usedaPd/MgLamixedoxidecatalystinSuzuki-Miyauracross-couplingreactionsofboronicacidswitharylhalides,aswellaswithbenzylbromide,inethanolusingpotassiumcarbonateortriethylamineasbases(Scheme11).114Thecatalystcouldbereusedseveraltimesandprovidedhighyieldsalsoifarylchlorideswereused.
Scheme11
PdcatalystsusingsepiolitesassolidsupportallowedtheSuzukireactionofiodobenzenewithphenylboronicacidtobecarriedoutwithoutusinganadditionalbase.57Reusageofsuchcatalystswaspossible,however,underconsiderablelossofactivity.Thecatalystcouldbereactivatedtoacertainextentwhenalkaliexchangedsepioliteswereused.
TheapplicationofaPdx-([PW11O39]7--([PW)y-KFcatalystobtainedbyfixingPdx11O39]7-)y-nanoparticlesonKFallowedthesynthesisofbiaryls51fromarylorheteroarylchloridesandphenylboronicacidundersolvent-freecondi-tionsinexcellentyields(Scheme12).45
Scheme12
2.3.PdonPorousAluminosilicatesZeolitesaswell-definedporousmaterialscanbeusedassupportsforPdassuchorinamodifiedmanner.Pd(II)onbasiczeoliteswasreportedintheSuzuki-Miyauracouplingofbromobenzenewithphenylboronicacidintoluene.115Noleachingwasobserved,andthesolidcatalystcouldbereusedafterwashingwithwater.Onlyaminordecreaseinthecatalyticactivitywasobserved.
Pd(II)-NaYzeoliteorPd(0)-NaYzeoliteperformedverywellinSuzukireactionsofarylbromideswithouttheadditionofaligand.116,117ThecatalystsexhibitedexcellentactivitywithK2CO3orNa2CO3asbaseatroomtemperatureallowinghighyieldstobeachievedaftershortreactiontimes.Howevertheywerelessusefulforarylchlorides.Itwasfoundoutthatthecouplingreactionsoccurredontheexternalsurface
144ChemicalReviews,2007,Vol.107,No.1ofthezeolites.Thesolidcatalystcouldbereusedafterregeneration(Table21).
Table21.Pd(II)-NaY-andPd(0)-NaY-CatalyzedSuzukiReactions
Pd(II)-NaYPd(0)-NaYAr-XAr′yielda(%)yielda(%)
4-MeOC6H4IC6H5>994-MeOC6H4BrC6H593(92)953-MeOC6H4BrC6H5972-MeOC6H4BrC6H5
85C6H5Br
4-MeC6H4(94)984-CNC6H4BrC6H590(78)1004-NO2C6H4BrC6H54-AcC6H4BrC6H5>5499(44)(88)51714-AcC6H4ClC6H526b
4-CF3C6H4Cl
C6H5
52b
a
GCyield,isolatedyieldsinparenthesis.bAt100°C.
Asafurtherwaytosolid-supportedPdcatalysts,thecomplexesPdCl2[Ph2P(CH2)4SO3Na]orKweredirectlyloadedtoalkylsulfonatedmesoporoussupports.Theresultingheterogeneouscatalystwasappliedtothecouplingof4-iodoanisolewithphenylboronicacid.118,119Itcouldberecycledandreused.Remarkably,therecycledcatalystsshowedanenhancedactivity.
2.4.PdonModifiedSilicaSilica-supportedPdcatalystsusefulforSuzukiandalsoothercross-couplingreactionscanbepreparedinvariouswaysprovidingdifferentstructures.Thus,Pdcandirectlybedepositedontosilica,oritcanbeanchoredasacomplexbyligands,whicharecovalentlylinkedtothesilica.Inthelattercase,postmodificationofmesoporoussilicaorsilicaspheresispossible,forexample,bygraftingaligand(suchasSH)separatedbyaspacer.Pd(II)finallyformsacomplexwiththissolid-supportedligand.Asanalternative,itisalsopossibletouseaPdcomplexwithareactivelinkersubstituent,whichcancovalentlybindtothemesoporoussilica.Asafurthermethodofcatalystpreparation,asol-gelmethodcanbeappliedusingtetraalkoxysilaneandaPdligand(e.g.,OHorstablecarbene)bearingaspacer-separatedfunctionalgroup,whichisabletoreactwiththetetraalkoxy-silane.Anamorphousmaterialisformed,whichistreatedwithPd(OAc)2toprovideacatalystonamorphoussilica.Inthesecases,Pdismainlyencapsulatedinthesilicamatrix.AhighlyactivePdcatalystonamorphoussilica(SiO2/TEG/Pd)forSuzukicouplingswaspreparedviaPdnano-particlesobtainedfromPd(PPh3)4intetra(ethyleneglycol)andtetramethoxysilane,whichbecomeencapsulatedinasilicamatrix.120Itwasefficientincouplingofaryliodidesandarylbromidesbutnotactiveenoughtowardarylchlorides.Thereusabilitywastestedinthecouplingofphenylboronicacidandmethyl4-bromobenzoate.Thecatalystcouldbereusedthreetimeswithoutlosingactivity(Scheme13).Pd(II)onsilicafixedbymercaptopropylligandsusingmercaptopropylsiloxanewaspreparedonmesoporoussilica(Pd-SH-FSM)andonamorphoussilica(Pd-SH-SiO2).TheactivityofthedifferentrecycledcatalystsPddepositedwereintheorderPd-SH-FSM>Pd-SH-SiO2>onnonfunctionalizedmesoporoussilica.ObviouslytheSHligandspreventformationoflessactivePdaggregates.In
YinandLiebscherScheme13.PreparationofSiO2/TEG/PdandItsUseasCatalystinSuzukiReactions
particular,Pd-SH-FSMhadbeenshowntoactasanactive,stable,andrecyclableheterogeneouscatalystsfortheSuzukireactionof4-bromoanisoleandphenylboronicacid.47
SuzukicouplingoflessreactivearylchloridesandbromidescouldbeachievedwithaPdcatalystonanothermercaptopropyl-modifiedmesoporoussilica(SBA-15-SH-Pd,Table22).121Itcouldbereusedfourtimeswithoutanylossofcatalyticactivity.Severalheterogeneitytests(hotfiltrationexperiments,three-phasetests)indicatedthatthemajorityofthecatalysis(>95%)occurredonthesupportedPd,butleachingwasalsofoundtoalowextent.
Table22.SBA-15-SH-Pd-CatalyzedSuzukiReactions
TtyieldaentryAr-X
solvent(°C)(h)(%)1chlorobenzene
DMF100246724-chloroacetophenoneH2O
100249634-bromoacetophenoneDMF/H2Ob80898c44-bromoacetophenoneH2O
80598d53-bromopyridineDMF/H2Ob90159864-bromotolueneDMF/H2Ob90158274-bromoanisole
H2O9015968
4-bromobenzaldehyde
H2O
90
15
97
a
Isolatedyield.bDMF/H2O(20:1).cRecyclesof1,2,3,and4gaveyieldsof97%,97%,95%,and95%.dRecyclesof1,2,3,and4gaveyieldsof99%,97%,96%,and92%.
Similartomercaptopropylligands,aminopropylligandsweregraftedtoamorphoussilicabyreactionwiththecorrespondingaminopropyltriethoxysilane.ThesemodifiedsilicawereloadedwithPdnanoparticlesbytreatingwithPd(OAc)2.ThesecatalystsworkedwellinSuzukireactionofarylbromideswitharylboronicacids(K3PO4,toluene,100°organicC)whenmodifiers.chelating122diaminesAnoptimalandcatalysttriaminescouldwerebeusedreusedasfourtimeswithoutasignificantlossofactivity,buttheactivitydecreasedinfurtherruns.
Electron-richimidazolidinecarbenePd(II)complexes54couldbegraftedontomesoporoussilicaviaapropyltri-ethoxysilanelinker(Scheme14).122,123Theresultingcatalyst55exhibitedexcellentactivityinSuzukicouplingofnon-activatedchloroarenes(Table23).123Thecatalystwasstableandcouldbereused.
Anotherveryeffectivecatalyst60(SiO2-OC-Pd)wasobtainedbyCorma,Garcı´aetal.bygraftingapreformedoxime-carbapalladacyclePd(II)complex58ontosilicausingamercaptopropyllinker(Scheme15).124Thecatalystpro-videdaquantitativeyieldintheSuzukireactionofp-chloroacetophenoneandphenylboronicacidinwater;leach-
HeterogeneousPdCatalyzedC−CCouplingReactionsScheme14.SynthesisofCarbene-PdComplexesFixedtoModifiedSiO2
Table23.SuzukiReactionsofChloroareneswithPhenylboronicAcida
Rcatalystyieldb(%)AcPd(OAc)2/5390Pdcomplex5586cOCH3Pd(OAc)2/5393Pdcomplex5588cCH3Pd(OAc)2/5391Pdcomplex5585cCHO
Pd(OAc)2/5397Pdcomplex55
90c
a
Reactionconditions:1.0mmolofchloride,1.5mmolofPhB(OH)2,3mLofdioxane.bIsolatedyield.cFourthrun.
ingwasnotfound,andthesamecatalystsamplewasreusedeighttimeswithoutdecreasedactivity(Table24).124
Scheme15.PreparationofSiO2-OC-PdCatalyst60
Table24.SiO2-OC-Pd-CatalyzedSuzukiReactionsinAqueousMedia
conditionsXt(h)conv(%)water/TBABBr162waterBr<0.1>99waterCl0.2591watera
Cl299water/dioxane(3:2)
Cl
0.25
55b
a
Catalystwasreusedeighttimes.bBiphenylwasdetectedasbyproduct.
Silica-supportedimidazole-palladacyclesSiO2-IM-Pd-H62andSiO2-IM-Pd-Me63(Figure2)exhibitedexcellentcatalyticactivity,recyclability,andstabilityinSuzuki-Miyauracouplingofarylbromidesandphenylboronicacid
ChemicalReviews,2007,Vol.107,No.1145(Table25).125,126Thecatalystshadverylowloadingofpalladiumandwereconsideredtobecompletelyheteroge-neousunderthereactionconditions.
Figure2.SiO2-IM-Pd-H,62,andSiO2-IM-Pd-Me,63.
Table25.SuzukiReactionsCatalyzedbyModifiedSiO2-SupportedPdComplexes
R
catalystt(min)yielda(%)H62(1.2mol%)18095CN62(1.2mol%)12092Cl62(1.2mol%)18088OMe62(1.2mol%)36079CH2Br62(1.2mol%)36060H63(0.4mol%)90100OMe63(0.4mol%)12092CN63(0.4mol%)6097PhCO63(0.4mol%)9095OH
63(0.4mol%)
90
85
a
GCyield.
Theimine-basedpalladacyclicsilico-supportedcatalysts65and66(Figure3)werefoundtobelessactiveinSuzukireactionsofarylbromideswithphenylboronicacidthantheirhomogeneouscounterparts.Thesecatalystsalsoexhibitedpoorrecyclabilityprobablybecauseoftheinstabilityofthecomplexliberatingzero-valentPdspeciesinthesolutionbyreductiveelimination.127
Figure3.Imine-basedpalladacycliccatalysts65and66.
2.5.PdonClaysandOtherInorganicMaterialsSepioliteclaysupportedPd(Pd(II)-sepiolite)couldeasilybeobtainedbytreatingtheclaywithaqueous[Pd(NH3)4]-Cl2anddryingundervacuum.IteffectivelycatalyzedtheSuzukicouplingofphenylboronicacidwitharylhalidesinDMFincludinglessreactiveelectron-richarylbromides(Table26).128ThecatalystexhibitedaremarkablyhighTON,andthuslowamountsofcatalystwerenecessary(0.02mol%).
Theunusuallyhighreactivityofelectron-richbromoarenesincomparisonwiththecommonlymuchmorereactiveelectron-poorbromoarenes(entries3-5versusentries6-7)suggeststhattheoxidativeadditionofarylhalidetothePd-catalystcannotbetherate-determiningstepinthesecases.Shimizuetal.alsoappliedPd(II)-sepiolitetotheSuzukicouplingof4-bromophenolwithphenylboronicacidorsodiumtetraphenylborateinwateratroomtemperatureinair.129ItprovidedhigheryieldsthanunsupportedPd(II)saltsandsomeothersupported-Pdcatalysts(Scheme16).
146ChemicalReviews,2007,Vol.107,No.1Table26.Pd(II)-Sepiolite-CatalyzedSuzukiCouplingofArylHalideswithPhenylboronicAcid
cat.GCentry(mol%)arylhalideT(°C)yield(%)TON10.02C6H5I10080400020.02C6H5Br
10081405030.024-NH2-C6H4Br10077
385040.024-MeO-C6H4Br10085(84)a425050.023-Cl-C6H4Br10091455060.024-Ac-C6H4Br10083415070.024-NO2-C6H4Br10091455080.14-Ac-C6H4Cl1002323090.001C6H5Br
1306565000100.0014-MeO-C6H4Br130565600011
0.001
4-Ac-C6H4Br
130
94
94000
a
Yieldofcycle2.
Scheme16.ComparisonofVariousCatalystsinSuzukiReactionof4-BromophenolwithPh4BNa
Pd(1.8%)onunmodifiedsilicacouldbeusedinaflowinjectionmicroreactorintheSuzukireactionof4-bromoben-zonitrilewithphenylboronicacidwithouttheadditionofanextrinsicbase.Thecatalystshowedalowleachrateandprovidedyieldsofabout67%.26
Clay-supportedPdcatalysts(Pd-PIC)canbeobtainedbyintercalationusingclayandPdCl2/Ph4P+Br-.ItprovidedgoodyieldsinSuzuki-Miyaurareactionsofaryliodidesorarylbromideswitharylboronicacids(Scheme17).130
Scheme17.Pd-PIC-CatalyzedSuzuki-MiyauraReactions
TreatmentofCa-deficienthydroxyapatiteCa9(HPO4)-(PO4)5(OH)(Ca/P)1.50,HAP-1)withanacetonesolutionofPdCl2(PhCN)2yieldedahydroxyapatite-supportedPdcatalyst(PdHAP-1),whichwashighlyefficientinSuzukicouplingofvariousarylbromideswithphenylboronicacid(Scheme18).131NoPdleachingwasobserved,andthecatalystcouldberecycled.
Mg-Al-layereddoublehydroxide(LDH)couldalsosuccessfullybeusedassolidsupportforPdasshownby
YinandLiebscherScheme18.PdHAP-1-CatalyzedSuzukiReactions
Choudaryetal.66Theligand-freeLDH-Pd(0)catalystswerepreparedbyanexchangeofPdCl42-followedbyreductionandexhibitedhighactivityinSuzukireactionsofchloro-arenes(Table27),aswellasinHeck,Sonogashira,andStillecouplings.Thecatalystshowedalmostconsistentactivityandselectivityincouplingreactionsofchlorobenzeneandphenylboronicacidafterreusingitinfivecycles.Itcouldalsobeappliedundernonaqueousionicliquidconditions.
Table27.LDH-Pd(0)-CatalyzedSuzukiCouplingofChloroareneswithArylboronicAcids
RAryield(%)HPh
93(92)aH3-NO2-Ph90H4-Me-Ph60H2-Naph80H
4-F-Ph704-OMePh
904-Ac
4-Me-Ph
88
a
UnderNAIL(nonaqueousionicliquid)conditions,8h.
3.HeckReactions3.1.PdonCarbon(Pd/C)TheHeckreactionisthemostpowerfulandwidelyusedmethodtocouplealkeneswithorganicmoietiesbearingasuitableleavinggroupsuchasahalide,atriflate,oradiazonium.Pd/Cwasappliedtothisreactioninthepioneer-ingworkofJuliaetal.asearlyasin197360,132andhasbeenthemostimportantheterogeneouscatalystsincethen,becauseitisefficientandcommerciallyavailable.Inthisearlyreport,styrenewasreactedwitharomaticchloridesandiodides.About50%yieldwasachievedinthemostfavorablecases.Itreached62%yield(82%conversionofstyrene)inpuremethanolat120°Candinanautoclaveunderpressure.Remarkably,itwasfoundthattheadditionoftriphenylphos-phine,whichisacommonligandinhomogeneousHeckreaction,inhibitsthereactionratherthanpromotingit(Scheme19).ThereforeitisnotsurprisingthatlateronPd/CwasusedinHeckreactionswithoutadditionalligands.
Scheme19.Pd/C-CatalyzedHeckReactionofChlorobenzenewithStyrene
Pd/C-catalyzedheterogeneousHeckreactionhasbecomesomaturedthatitisappliedinthecouplingof1-bromo-4-methoxybenzenewithoctylacrylate6,30fortheindustrialproductionofoctyl4-methoxycinnamate75,acommonUV
HeterogeneousPdCatalyzedC−CCouplingReactionsabsorberutilizedinthemanufactureofsunscreenlotion(Scheme20).
Scheme20.HeckReactionof1-Bromo-4-methoxybenzenewithOctylAcrylate
Ko¨hleretal.providedaverydetailedinvestigationabouttheapplicationofPd/CintheHeckreactionofarylbromideswitholefins.28,50AvarietyofPd/CcatalystsdifferinginPddispersion,Pddistribution,Pdoxidationstate,andwatercontentweretested.Theexperimentalresultsindicateda(quasi-)homogeneousreactionmechanism,thatis,thePdcomplexorcolloidalparticlesinsolutionactasthecatalyti-callyactivespecies.E105CA/W5%PdfromDegussaAGturnedouttobethebestPd/Ccatalyst.IthasahighPddispersion(36%),alowreductiondegree[mainlyPd(II)],andahighwatercontent(∼55%).ItshighcatalyticactivityinN-methylpyrrolidone/sodiumacetateat140°Callowedworkingwithextremelylowcatalystconcentrations(Table28).AnargonatmospherehelpstodecreasethePdleachingwhilemaintainingthehighactivity.Undertheseoptimizedreactionconditions,turnovernumbers(TON)upto-361000andturnoverfrequencies(TOF)upto18000h(forbromobenzene)wereachievedusingaPdconcentrationaslowas0.0025mol%(Table28,entry3).Completeconversionwasachievedforactivated(electron-withdrawingsubstituents)andnonactivated,aswellasdeactivated,bromoarenes(electron-donatingsubstituents)withinafewhours.Theextraordinarilyhighactivityseemstobecon-nectedwithdissolution-reprecipitationprocesses,wheredissolvedPdspeciesformedatthistemperaturearetheactivespecies.Muchlowercatalyticactivity(TONandTOFreducedbymagnitudes)inHeckcouplingwasfoundwithpre-reducedPd/Ccatalysts(Table28,entries4and5)inaccordancewithpreviousfindings.11
Table28.EffectofReactionConditionsontheHeckReactionofArylBromideswithStyrene81
catalystconvyielda
(%)entryR(mol%)T(h)(%)767778
TONTOF
1Ac0.00549690051920048002H0.005190831618000180003H0.0025290831636000180004bH1.0205852055835cH1.02012100112<16Cl0.056100921720003337OMe0.05292801918409208
OMe
0.01263630772003600
a
YieldsfromGLCanalysis.bReducedunderH2atmosphereat300°Cfor1h.cTreatedunderN2atmosphereat500°Cfor1h.
EvidencefordissolvedPdspeciesformedbyleachingfromPd/CbeingtheactivemoietiesinHeckreactionswasalsofoundbyAraiandco-workers11incaseofaryliodidesinN-methylpyrrolidoneinthepresentoftriethylamineorNa2-CO3asbase.However,almostalldissolvedPdspeciesre-depositedontothesurfaceofthesupportafterthereactionhadbeencompleted.Thus,thecatalystswererecyclable
ChemicalReviews,2007,Vol.107,No.1147withoutlossofactivity.Lowactivitiesanddehalogenationwereobservedforarylbromidesandarylchlorides.Ontheotherhand,4-nitrochlorobenzeneandvinylalkyletherasmorereactivereactantscouldbecoupledintoluene/triethyl-amineunderpressure,butwithlowregioselectivity(Scheme21).133-135Theseconditionswerealsosuccessfulinthecouplingofaroylchlorideswithbutylvinylether(Scheme21).133-135Inthesecases,alsootherheterogeneousPdcatalystswereinvestigated,showingthatthetypeofsolidsupportaffectstheregioselectivityofthecoupling.51,136However,theheterogeneouscatalystswerelessregioselectivethanthehomogeneoussystembasedonPd(OAc)2.
Scheme21.Pd/C-CatalyzedHeckReactionsofVinylAlkylEthers
AdvantageoverhomogeneouscatalysiswasfoundwithPd/CintheHeckreactionof4-and2-iodopyrimidines83and85withmethylacrylate.137Highyieldswereobtainedandhomocouplingwasnotobserved(Scheme22).
Scheme22.Pd/C-CatalyzedHeckReactionsofIodopyrimidineswithMethylAcrylate
TheapplicationofultrasoundinPd/C-catalyzedHeckreactionscanbeadvantageousasdemonstratedforthereactionofiodobenzenewithmethylacrylateinNMP.138Therateofthereactionincreasedandthecatalystshowedhighactivityunderambientconditions(airandmoisture).Itcouldbeconvenientlyseparatedfromthereactionmixtureandreused(Scheme23).
Scheme23.HeckReactionofIodobenzenewithMethylAcrylateunderUltrasound
AsshownbyBellerandKu¨hlein,heterogeneousPd/CcatalysiscanalsobeappliedtotheHeckreactionofaryldiazoniumsalts88.139Excellentyieldswereobtainedwithacrylateasreactantwithoutusingabaseorphosphineligand(Table29).Interestingly,nodifferenceinreactivityinrelationtotheelectronicnatureofthediazoniumcompoundwasobserved.ThiseffectmakesitverylikelythatforthistypeofHeckreaction,contrarytothereactionofarylhalides,
148ChemicalReviews,2007,Vol.107,No.1Table29.Pd/C-CatalyzedHeckReactionsofDiazoniumSaltswithAcrylates
a
Isolatedyield.
theinsertionofthepalladiumcatalystisnottherate-determiningstep.
Ionicliquidshaveattractedgrowinginterestasenviron-mentallybenignreusablesolvents.140,141Becauseoftheirhighlypolarnature,theyarepromisingactivatingandstabilizingsolventsforPd/C-catalyzedHeckreactions(Table30).12Thereactionwascarriedoutsimplybyheatingasolutionofanarylsubstrate,anolefin,andabaseinanionicliquid([bmim]PF6)with3mol%of10%Pd/C.Pd/Cdispersedwellin[bmim]PF6.Afterthereaction,theproductwasextractedsimplybystirringwithn-hexaneordiethyletherseveraltimesfollowedbydecantationoftheupperorganiclayer.Noaqueousworkupwasrequired.ThePd/Cwaskeptandsuspendedcompletelyintheionicliquidlayeraftertheextraction.
Table30.Pd/C-CatalyzedHeckReactionsofArylHalideswithEthylAcrylateinIonicLiquids
Ar,XT(°C)t(h)yield(%)Ph,I
1001924-Me-Ph,I10012534-MeO-Ph,I10012694-Ac-Ph,I1002465Ph,Br
14012404-NO2-Ph,Br14012853-Cl-Ph,Br14012524-MeO-Ph,Br
140
12
25
Aryliodidesgavehigheryieldsthanbromides.Aryltriflatesresistedthereactionandwererecoveredcompletelyevenat140°Cwithorwithoutaphosphineligand.12SincePd/Cremainedonlyinionicliquid,theionicliquidcontainingPd/Ccanbereusedascatalystsystemitself(Table31).Althoughacertaindecreaseinyieldswasobservedafterthesecondreuse,probablyduetoaccumulationoftriethylam-moniumiodide(Table31,entries3-5),washingtheionicliquidlayerwithwaterrecoveredthecatalyticactivitytothesamelevelasinthefreshsystem(entry6).
Itwasfoundbyinductivelycoupledplasma(ICP)emissionspectroscopythatafterfiltrationofthePd/CtheconcentrationofPdbeforeandaftertheHeckreactionwasnegligible.TheauthorsconcludedthattheHeckreactionwascatalyzedbythePdatthesurfaceofPd/C.
YinandLiebscherTable31.Pd/C-CatalyzedHeckReactionsofIodobenzenewithEthylAcrylateinIonicLiquidbyaRecyclableCatalyticSystementryrecyclesT(°C)t(h)yield(%)1010012952110012933210012844310012815410012806a
5
100
12
95
a
Catalyticsystemwaswashedwithwaterbeforeuse.
Pd/C-catalyzedHeckarylationof2-methylprop-2-en-1-olwith1-tert-butyl-4-iodo-benzeneinanionicliquidresultsintheformationofthefragrance-Lilial91.69Higheractivitywasobservedinionicliquidmedia,andthecatalystcouldbereusedwithonlymarginaldecreaseinyieldandselectivity(Table32).
Table32.Pd/C-CatalyzedHeckReactionof
1-(tert-Butyl)-4-iodobenzenewith2-Methylprop-2-en-1-olinIonicLiquids
runconv(%)select.(%)
196962949539593491935
93
92
InHeckreactionscatalyzedwithPd/C,ionicliquidmethodologycanbecombinedwithmicrowaveheating.68Thereactionwasconductedinanopensystemwith5%Pd/Cascatalyst.Modesttogoodyieldsofcouplingproductswereobtainedinshortertimes(Table33).Thereactivityofthehalobenzenesfollowedtheusualsequence,thatis,electron-withdrawingsubstituentsincreasethereactivityandelectron-donatingsubstituentsdecreaseit.Iodoarenesreactfasterthanbromoarenes,whilechloroarenesonlyreactifsubstitutedbystrongelectron-withdrawinggroups(entries9-11).Allofthereactionswentsmoothlyandthe(E)-butylcinnamates92weretheonlyproducts.Reactiontimesareveryshort,andthecatalystsystemcouldbereused.
Table33.Pd/C-CatalyzedHeckReactionsinIonicLiquidbyMicrowaveIrradiation
entryArXt(min)yielda(%)1Ph
I1.58622-MeO2C-PhI1.5353Ph
Br1.58044-NO2-PhBr1.58954-Ac-PhBr1.561
64-OMeBr1.530(56)b74-MeBr1.53382-NaphBr1.5799Ph
Cl2.00b
104-NO2-PhCl2.027(42)b11
4-CHO-Ph
Cl
2.0
0
a
Isolatedyield.bUnder375Wofmicrowaveirradiation.
HeterogeneousPdCatalyzedC−CCouplingReactionsAsanothertechniqueworthmentioning,thePd/Ccatalystiskeptinaseparateliquidtriphasesystem.Inisooctane/water/Aliquat336(methyltrioctylammoniumchloride),142itwasfoundthattherateofHeckcouplingofaryliodideswitholefinswasaccelerated10-foldinthepresenceofAliquat336.BothwhenconductedinA336assolventandwhenconductedinanisooctane/A336/watertriphasicmixture,theHeckreactionofaryliodideswithelectron-deficientolefinsproceededwithhighyieldsandselectivities(Table34).
Table34.TriphaseHeckCouplingofArylIodideswithEthylAcrylatea
yieldentryRA336T(h)(%,GC)1Hno1.5520172Hyes1.530209434-NO2nob6.01044-NO2yesb3.07854-Acyes208064-Clyes207874-OMeyes206884-NH2yesb20689
3-CN
yes
20
81
a
Reactionconditions:aryliodide(1.0mmol),ethylacrylate(1.5mmol),Et3N(1.5mmol),Pd/C(0.05mmol),10mLofisooctane,5mLofwater,A336(0.30mmol).bSincethesubstrateisinsolubleinisooctane,toluenewasused.
PdongraphitewaspreparedbyreductionofPdCl2byC8Kandcouldbeused(7mol%catalyst)inHeckreactionsofacrylates,fumarates.andstyrenewitharylorvinyliodidesinthepresenceoftributylamine.143
3.2.PdonMetalOxidesThefirstreportaboutaheterogeneousHeckreactionusingPdsupportedonmetaloxidewaspublishedbyKanedaetal.in1990.144Chlorobenzenewascoupledwithstyreneinmethanolat150°CusingPd/MgOascatalystandNa2CO3asbase.Lateronseveralmetaloxides(MgO,Al2O3,SiO2,TiO2,ZrO2,ZnO,mixedMgLaO,etc.)havebeenusedassupports)I,Br,Cl,forOTf,PdcatalystsCOCl,SOinHeckreactions.Ar-XwithX2Cl,orN2BF4werecoupledwithacrylates,12,19,38,55,67,145-147acrylonitrile,52,53,55styrene,20,21,55,146,147vinylalkylether,51,55,136terminalalkenes,55andcycloal-kenes.27Biffisandco-workersreviewedpalladiummetalcatalystsinHeckreactionsin2001.10
Mostapplicationswereperformedunderligand-freeconditions.DetailedstudiesofKo¨hlerandco-workersoncatalystefficiencyandonoptimizationofHeckreactionofbromobenzenewithstyrenecatalyzedbysolid-supportedPd(5%Pd(w/w)inDMF/NaOAc,140°C,20h)revealedthefollowingorderofeffectiveness:20,21
Pd/C>Pd/TiO2>Pd/ZrO2>Pd/MgO>Pd/ZnO>
Pd/SiO2
AdifferentorderwasfoundinHeckcouplingofiodobenzenewithacrylonitrileinthepresenceofPPh3(5%Pd,Et3Nasbase,CH3CN,140°C,14h)byWaliandco-workers:52
ChemicalReviews,2007,Vol.107,No.1149Pd/MgO>Pd/γ-Al2O3>Pd(acac)2>Pd/C>
Pd/CaCO3
Ko¨hlerandco-workersreportedforthefirsttimethatspecificallypreparedheterogeneousPd/MOxcatalysts(M)metalcenter)convertedevennonactivatedarylchloridesintostilbenesinHeckreactionswithstyrene.Shortreactiontimesandremarkablylowamountsofcatalystsweresufficient.85,148Thehighlyactivepalladiumspeciesweregeneratedinsitubydissolutionfromthesupportandstabilizedagainstagglomerationbyreprecipitationonthesurface.Theseprocessescouldbecontrolledbyaspecificchoiceofcatalystandtuningthereactionconditions.Evidencewasfoundthatthesolidcatalystfunctionsasareservoirformolecularpalladiumspeciesinsolution.Theirconcentrationinsolutioncorrelateswiththeprogressofthereactions.Kineticinves-tigationoftheHeckreactionofbromobenzenewithstyreneshowedthatonlyalittlepalladiumleachedtothesolutioninthestartingperiod.Afterthereactiontemperaturereached140°C,21aboutone-thirdofthepalladiumwasleachedfromthesurfaceofthesupport.Simultaneously,themajorityofthearylhalidewasconverted.Afterthereactionwasfinished,thepalladiumwasre-depositedontothesupporttoagreatextent.
Analogousinvestigationswereperformedwithdifferentarylchloridesundermodifiedconditionsaffordingcompa-rableresults(Table35).148
Table35.HeckCouplingofArylBromidesandChlorideswithStyrene
cat.conc.T(°C),convyieldentryR,Xcatalyst[mol%]baset(h)(%)(%)1H,BrPd/TiONaOAc140,495862H,Br2a0.0011Pd/Al0.0009NaOAc140,496873bAc,ClPd/Al2O3a0.01Ca(OH)160,298904bAc,Cl2O3aPd/Al0.01Ca(OH)2160,287835Ac,Cl2O3cPd/NaY0.005Ca(OH)2160,299956bH,ClPd/NaY0.05Ca(OH)2160,649457bH,ClPd/NaY0.05Ca(OH)2160,68583d8b
Me,Cl
Pd/NaY
0.05
Ca(OH)22
160,6
40
36d
a
PrecipitationofPd(OH)2onMOx.bAdditionofTBAB.cPreparedbycoprecipitation.dUnderO2atmosphere.
ArecentlydevelopedPdcatalystonMg-LamixedoxideturnedouttobesuperiorforHeckcouplingofactivatedandinactivatedaryliodides,bromides,andchloridesevenatlowtemperatures(80°C)underambientatmosphere(Scheme24).55HighE/Zratiosofproducts95wereobservedinmostcases,dependingonthenatureofalkene.Thesolventhadadeterminanteffectontheyield.Thecatalystcouldbereusedwithoutadditionalactivationfourtimeswithoutasignificantlossofactivityandcouldbestoredunderairwithoutproblems.
Scheme24
150ChemicalReviews,2007,Vol.107,No.1MicrowaveirradiationcanbeappliedtoHeckreactioncatalyzedbyPdonseveralmetaloxidesasshowninthecouplingofiodobenzenewith1-decene.52Slightlyhigheryieldswereachievedinthemicrowave-mediatedsolventlessHeckreactionofaryliodideswithmethylacrylateinthepresenceofpalladiumonKF/alumina(Scheme25).
Scheme25.PalladiumonKF/Al2O3CatalyzedHeckReactionsunderMicrowaveIrradiation
TheapplicationofnonaqueousionicliquidscanbeadvantageousinheterogeneousHeckreactions.Silica-supportedpalladiumcomplexes(Pd(II)/SiO2)exhibitedhighercatalyticactivityinHeckreactionsofaryliodideswithacrylatesinanionicliquid([bmim]PF6)thaninDMF(Table36).67
Table36.Pd(II)/SiO2-CatalyzedHeckReactionsofArylIodideswithAcrylatesUsingIonicLiquids
RR′solventt(h)conv(%)HMe[bmim]PF6198HMeDMF
188HBu[bmim]PF6170HBuDMF
1674-MeEt[bmim]PF62994-MeEtDMF
2784-OMeEt[bmim]PF66794-OMeEtDMF
6854-AcEt[bmim]PF66334-Ac
Et
DMF
6
99
Pdcomplexescanalsobesupportedbyironoxide-silicananoparticles.ThusaPdcatalystconsistingofmagneticmaghemite(γ-Fe2O3),silica,andatetheredheterocycliccarbene(imidazole)ligand(Fe2O3-Si-Pd)gavegoodresultsinHeckreactionsofaryliodidesorarylbromideswithn-butylacrylate(Table37,seealsoFigure1).110
Table37.Maghemite-SilicaNanoparticle-SupportedPd-CatalyzedHeckReactions
isolatedRXyield(%)2-MeI90a2-MeBr883-OMeI893-OMeBr904-Ac
I
88
a
GC-analysisrevealed97%yieldinthefirstrunand97%,95%,94%,and92%inthesecondtofifthrounds,respectively.
Silicasol-gelencagedPd(PPh3)2Cl2couldbeusedasarecyclablecatalystwithoutlossofcatalyticactivityinHeckreactionofaryliodideswithstyrene.149ItwaspossibletocombinetheHeckreactionwithsubsequentphotocyclizationinaone-potprocessaffordingphenanthreneandchrysene99(Scheme26).149
YinandLiebscherScheme26.One-PotSynthesisofPhenanthreneandChrysenebyHeckCouplingandPhotocyclization
3.3.SupportsPdonMicroporousandMesoporousPdonmolecularsievesascatalystsinheterogeneousHeckreactionswasfirstinvestigatedbyMehnertandYing.15,145Palladiumcatalystssupportedonaniobium-modifiedme-soporoussilicalite(Nb-MCM-41)werepreparedbyvaporgrafting.ThesemesoporousmaterialsshowedremarkableactivityinHeckreactionsofbromoareneswithelectron-withdrawingsubstituentsinp-position.
Pappandco-workerspreparedaheterogeneousligand-freePd-MCM-41system,whichcouldbeusedasanefficientandrecyclablecatalystinHeckreactions.Palladiumloadingsof1.39%,3.0%,and5.85%showedhighactivityandselectivityintheHeckcouplingofiodobenzenewithstyrene(conversionsof76-84%,selectivitiesof84-87%)andmethylacrylate(89-100%conversionsand100%selectivi-ties).146Moreover,thesecatalystsperformedwellinHeckreactionsofactivatedbromoarenes(4-bromonitrobenzeneand4-bromoacetophenone).Inallreactions,complete(E)-selectivitywasobserved.R-Couplingwasobservedasasidereactioninthecaseofstyrene.Itwasfoundthatthecatalystactivitiesdependonpalladiumloadingandmetaldispersion.Inmostcases,catalyticperformanceof3.0%Pd-MCM-41withlowerPddispersionshowedloweractivity.AseriesofotherbromoareneswereinvestigatedintheHeckcouplingofstyreneandmethylacrylateusing1.39%Pd-MCM-41catalyst(Table38).Importantly,thecatalystsarestableunderthereactionconditionsandretainhighactivityandselectivityforatleast20successiverunswithouttheneedtoexcludeairormoisture.146
Table38.HeckReactionofBromoarenesover1.39%Pd-MCM-41Catalysta
ArRt(h)conv(%)select.(%)PhCO2Me38696Ph
Ph693934-CN-PhCO2Me39793Ph690954-MeO-PhbCO2Me382944-MeO-PhbPh691894-Br-PhcCO2Me3100934-Br-PhcPh685924-Cl-PhCO2Me3641004-Cl-PhPh654911-NaphCO2Me31001001-NaphPh610092pyrid-3-ylCO2Me2294100pyrid-3-yl
Ph
22
57
93
a
Conditions:1equivofArBr,1.2equivofalkeneandNa2CO3,0.2equivofBu4NCl,and0.3mol%Pd.bWithoutBu4NCl.cWithoutBu4NCl,withNaOAcasthebase.
HeterogeneousPdCatalyzedC−CCouplingReactionsDjakovitchandKo¨hlerstudiedaseriesofpalladiumcatalystsobtainedbyionexchangeatNa-orH-zeolites(mordenite,Y)withPd(NH3)4Cl2.Pd-modifiedzeolitesexhibitedahighactivitycomparabletohomogeneouscatalysistowardtheHeckreactionofarylbromideswithstyreneforsmallPdconcentrations.10,16-18,21,27Thezeoliteobviouslycontrolledtheselectivityofthereaction.16Reactiontemperatureplaysanimportantrole.Nosubstantialleachingwasobservedinmostcases.ButevidencefordissolvedmolecularPdspeciesbeingresponsibleforthecatalysiswasfound.27Thecatalystscouldbeeasilyseparatedfromthereactionmixtureandreuseduptofivetimeswithoutaconsiderablelossinactivity.SomeoftheresultsaresummarizedinTable39.16,18ThecatalystcouldalsobeappliedtoHeckcouplingof4-chloroacetophenonebutdidnotperformsowellevenathighertemperatures.18
Table39.HeckReactionofVariousArylBromideswithAlkenesbyPd-ZeoliteCatalysts
TGLCyielda(%)Pd-zeoliteR
R′
(°C)101102103[Pd(0)]-NaY
FPh14089.4(86.0)0.98.2[Pd(NH3)4]2+-NaYFPh10014085.193.0(80.1)(80.9)1.01.07.98.810094.5(89.5)0.76.7[Pd(OAc)2]-NaYFPh14079.2(81.2)0.97.2[Pd(NH3)4]2+-NaYOMePh10014057.681.2(39.9)(75.8)0.49.53.99.5[Pd(NH3)4]2+-NaYNOPh[Pd(NH3)4]2+-NaYH2Ph14014094.884.9(89.8)(75.8)1.10.74.16.5[Pd(NH3)4]2+-NaYHBuO14025.720.412.4[Pd(NH3)4]2+-NaY
H
CO2Me140
91.0(69.4)0.50.4
a
Isolatedyieldsinparenthesis.
K+-andCs+-exchangedX-zeolitescontainingPdCl2(bifunctionalcatalysts)developedbyGarciaandco-workersallowedimplementationoftheHeckreactionofiodo-andbromobenzenewithstyreneintheabsenceofanextrinsicbase.49Obviously,sitesofthesupportactasbaseinthesecases.Noleachingwasobserved.Theactivityoftheusedcatalystcouldberegainedtoalargeextentbyreactivationbywashingwithwater.Asanalternativetostyrenes104,theformationof1,1-diphenyletheneregioisomercanbefavoredbyhighPdloadings(Scheme27).TheauthorsalsoinvestigatedtheeffectofporesizeandPdloadingofdifferentzeolitesonthecatalyticactivity.WhenDMFwasusedassolvent,thecatalyticactivitywasmainlyattributedtoleachedPd.
Scheme27
IncontrasttotheconclusionsofDjakovitchandKo¨hlertothenatureofcatalysisofPdonzeolites(molecularPdspeciesinsolution,Videsupra),Damsandco-workers.61,150andOkumura84etal.assumedthattheheterogeneousnature
ChemicalReviews,2007,Vol.107,No.1151ofthecatalysiswithPd-zeolitesinHeckreactionslargelydependedonthepretreatmentofthecatalyst,theoxidationstateofPd,thesolvent,andthebase.ForacriticalreviewaboutthissubjectfavoringhomogeneouscatalysisasthegeneralmodeofactionseeJonesetal.36TheexcellentperformanceofPd(0)/HYwasattributedtotheformationofstablePd13clusterskeptinsidethesupercageofHY.84ThiscatalysthadtobegeneratedbycalcinationinO2andreductionbyH2beforeitcouldbereused.Withtributylamineasthebaseintoluene,theHeckolefinationY,ZSM-5)withPd-(NH3)42+-zeolites(0.4wt%Pd;mordenite,andPd(0)-mordenite(0.4and4wt%Pd)wereconcludedastrulyheterogeneous.61,150Pdleachingfromthezeoliteswasevaluatedinaverystrictfiltrateactivitytest.ItwasclearlyrelatedtothepresenceofoxidizedPd(II)inanall-oxygenenvironment,thatis,ionicPd(II)orPdO.Theheterogeneousreactionswiththezeolite-supportedcatalystcanbeacceler-atedbytheadditionofaquaternaryammoniumsaltpromoter.ThecatalyticactivityofPd-zeolitesinHeckreactionfollowedtheorder
Pd(NH2+3)4-Y>Pd(NH3)2+4-mordenite>
Pd(NH3)2+4-ZSM-5
Pdonporousglassservedasauseful,reusablecatalystforHeckreactionofiodobenzeneand4-bromoacetophenonewithstyreneandallylicalcoholallowingthereactiontobecarriedoutinthepresenceofair.24
3.4.HybridPdSupport)onModifiedSilica(Organic−InorganicOrganochemicallymodifiedsilicacanalsoserveassolidsupportforPdcatalysts.Silicawasmodifiedbyvariouschlorohydrosilanes(trichloro-,dichloromethyl-,chlorodi-methyl-,dichlorophenyl-,andchlorodiphenylsilane).Theresultingmaterials,whichweremodifiedatthesurfacebymethylorarylgroups,weretreatedwithsaturatedsolutionsofPdCl2inmethanoltoformdifferentPd-on-silicacatalystswithvariousPdloadings(Pd/SiO2Me,Pd/SiO2Me2,Pd/SiO2-Ph,Pd/SiO2Ph2).
Pd/SiO2PhexhibitedhighcatalyticactivityintheHeckreactionofaryliodidesandbromideswithstyreneormethylacrylate(Table40).151,152Thecatalystcouldberecoveredandreused.
Table40.CatalyticPerformanceof0.3%Pd-SilicaCatalystsinHeckCoupling
Pdcat.R1,XR2t(h)conv(%)select.(%)
Pd/SiO2MeH,ICO2Me28499Pd/SiO2Me2H,ICO2Me25499Pd/SiO2PhH,ICO2Me29799Pd/SiO2Ph2H,ICO2Me25199Pd/SiO2MeNO2,BrCO2Me210099Pd/SiO2Me2NO2,BrCO2Me26899Pd/SiO2PhNO2,BrCO2Me210099Pd/SiO2Ph2NO2,BrCO2Me26699Pd/SiO2MeAc,BrCO2Me26799Pd/SiO2PhAc,BrCO2Me27599Pd/SiO2MeH,IPh55886Pd/SiO2Ph
H,I
Ph
5
80
83
Asanalternativetomercaptopropylmodification,alsoarsanopropylormethylselenoundecylgroupswereintroduced
152ChemicalReviews,2007,Vol.107,No.1intosilicaandallowedtoactassolidsupportforPdasshownbyCaietal.(Figure4).Inallthesecases,thePdis
Figure4.Threekindsofmodifiedsilicasupportedpalladiumcatalysts.
complexedbythedonoratomsoftheorganicmodificationofthesilica(S,As,Se).ThesecatalystsexhibitedhighactivityandselectivityintheHeckcouplingofaryliodidesandbromides(Table41)andcouldeasilybeseparatedandreused.153-156
Table41.HeckReactionCatalyzedby“Si”-X-Pd(0)Complexa
cat.X(concn,yieldbentrymol%)R,XR′T(°C)t(h)(%)ref1SH(0.4)H,IPh1006921532SH(0.4)OMe,IPh1006901533SH(0.4)H,ICO2H1006951534SH(0.4)OMe,ICO2H1006921535As(0.6)H,IPh1006921546As(0.6)NO2,BrPh14012751547As(0.6)H,ICO2H1006941548As(0.6)NO2,BrCO2H14012791549As(0.6)H,ICO2Bu10069015510As(0.6)NO2,BrCO2Bu140127815511As(0.6)H,ICO2NH210069015512As(0.6)NO2,BrCO2NH2140127615513Se(0.4)H,ICO2Bu10069015614Se(0.4)NO2,BrCO2Bu140127815615Se(0.4)H,ICO2NH210068915616
Se(0.4)
NO2,Br
CO2NH2
140
12
83
156
a
Reactionconditions:arylhalide(5mmol),olefin(5.5mmol),andBu3N(6mmol)in1.0mLofp-xyleneorDMFwereused.Whenarylbromidewasused,PPh3(0.05mmol)wasadded.bIsolatedyield.
MesoporoussilicawasmodifiedbymercaptopropylsilaneandtransformedintoPd(II)complexes(Pd-SH-FSMandPd-SH-SiO2).Suchsolid-supportedPdcomplexescanactasactive,stable,andrecyclableheterogeneouscatalystsintheHeckreactionsof4-bromoacetophenoneandethylacrylate.47ThekineticresultsobtainedwiththefreshPdcatalystsexhibitedthefollowingorderofcatalyticactivity:
Pd-SH-FSM)Pd-FSM>Pd-SH-SiO2)Pd/C>
Pd-Y
ForthefreshPd-SH-FSMcatalyst,TONandTOFwereobtainedas73000and36000h-1,respectively.The“hotfiltrationtest”demonstratedthatPd-SH-FSMwasatrueheterogeneouscatalyst.Pd-SH-FSMandPd-SH-SiO2showedexcellentrecyclabilityintheHeckreactionof4-bromoacetophenonewithethylacrylate(Table42).46Thecatalystscouldbereusedatleastfivetimeswithnoindicationofdeactivation.YinandLiebscherTable42.HeckReactionUsingRecoveredCatalysts
yielda(%)yielda(%)cycle(Pd-SH-FSM)
(Pd-SH-SiO2)
fresh9284firstreuse9593fifthreuse
97
95
a
DeterminedbyGC.
Mercaptopropyl-modifiedmesoporoussilicaPdcomplex,SBA-15-SH-Pd,121andaminopropyl-modifiedmesoporoussilicaPdcomplexes,SBA-15-NH2-Pd121orY-NH2-Pd,157werealsoefficientreusablecatalystsinHeckreactionsofnonactivatedarylbromidesoriodobenzene(Table43).
Table43.SBA-15-ModifiedPdCatalystsfortheHeckReactions121a
entry
R,Ycatalyst(loading)yield(%)1H,BrSBA-15-SH-Pd(1%)952COMe,BrSBA-15-SH-Pd(0.5%)963COMe,Brreusedfromentry2934H,ISBA-15-NH2-Pd(1%)965
H,Br
SBA-15-NH2-Pd(1.5%)
97
a
Reactionconditions:1mmolofhalide,1.5mmolofolefin,2mmolofNaOAc.
Silicawasalsomodifiedbytetherediminepallada-cycles158,159orSCS-N-pincercomplexes48(Figure5)toprovidesolidsupportsforPdinHeckcouplingreactions.ThesecatalystsexhibitedhighcatalyticactivityinHeckreactionsofaryliodidesandactivatedarylbromidesandcouldbereusedwithoutsignificantlossofactivityandselectivity(Table44).
Figure5.Fourkindsofmodifiedsilicatetherediminepallada-cycles.
Asanotherpossibility,reversephasesilicaobtainedbytreatmentwithalkyltrimethoxysilanescanbeusedassolidsupportforPd.Triarylphosphinesservedasexternalligandsinthesecases.Highyieldswereachievedwitharyliodideorbromides(Scheme28).160
PdnanoparticlesencapsulatedinsilicamatricescouldbegeneratedfromPd(PPh3)4inamixtureoftetra(ethyleneglycol)(TEG)andtetramethoxysilaneandfinaltreatmentwithwater.120Duringthisprocess,PPh3wasoxidizedtothetriphenylphosphineoxide,whichwasrecoveredfromthefinalfiltrateofthecatalystpreparationinmorethan90%
HeterogeneousPdCatalyzedC−CCouplingReactionsTable44.HeckReactionsbyModifiedSilicaSupportedIminePalladacyclesa
T(°C),conventryR,Xcatalystsolventt(h)(%)1H,ISiO2-IM-Pd-HMeCN82,2482(0.2mol%)2H,ISCS-N-pincerDMF120,2933OMe,IPd-2QC
NMP130,398(0.01mol%)4OMe,IPd-2PC
NMP130,399(0.01mol%)5Me,IPd-2QC
NMP130,1100(0.1mol%)6Me,IPd-2PC
NMP130,1100(0.1mol%)7NO2,BrPd-2QC
NMP130,195(0.1mol%)8NO2,BrPd-2PC
NMP130,190(0.1mol%)9Ac,BrPd-2QC
NMP130,151(0.1mol%)10Ac,BrPd-2PC
NMP130,146(0.2mol%)11H,BrPd-2QC
NMP130,2432(0.2mol%)12
H,Br
Pd-2PC
NMP
130,24
30
(0.1mol%)
a
Entry1isfromref158;entry2fromref48;othersarefromref159.
Scheme28.PreparationofReversePhaseSilicaSupportedPalladiumCatalystsandTheirApplicationtoHeckReactions
yield.Thisheterogeneouscatalyst(SiO2/TEG/Pd)showedhighactivityintheHeckcouplingreactionsofaryliodideswithstyrene(Scheme29).120
Scheme29.SiO2/TEG/Pd-CatalyzedHeckReactionofArylIodidewithStyrene
AsanotherwayoffixingPdtomesoporoussilicaSBA-15,SiHgroupswereintroducedbyreactionwithtrimethoxy-silane,whichreducePd(OAc)2.AsshownbyShietal.,thisprocedureresultsinthedepositionofmetalcolloidlayersontheporewalls,creatingoneofthemostactivehetero-geneouscatalystsforHeckreactions.147,161Excellentyieldswereachievedinthecouplingofiodo-andbromoareneswithstyreneormethylacrylate,evenwhenlowamountsofcatalystwereusedandthecouplingwascarriedoutinair(Scheme30).Thecatalystcouldeasilybeseparatedbyfiltrationandreusedatleastfivetimeswithoutasignificant
ChemicalReviews,2007,Vol.107,No.1153Scheme30
lossofactivity.Indicationsforheterogeneitywerefound,althoughsmallamountsofleachedPdcouldbedetectedinthereactionmixtureofthefirstrun.
3.5.PdonClayandOtherInorganicMaterialsMg-Al-Layereddoublehydroxidesupportedpalladiumnanoparticles(LDH-Pd(0)),developedbyChoudaryetal.,servedasversatilecatalystsinligand-freeHeckcouplingsofvarioussubstitutedchloroarenesandolefinsundernon-aqueousionicliquid(NAIL)conditions(Table45).66Thereactivityofthesechloroarenesiscorrelatedtotheelectrondensityofthearomaticring.ThecatalystwasreusedforfivecyclesintheHeckolefinationof4-chloroanisolewithstyreneundermicrowaveandthermalconditions.Thehigheref-ficacy,asdisplayedinthenonaqueousionicliquidundermicrowaveconditions,isascribedtotheionicconductance.
Table45.LDH-Pd(0)-CatalyzedHeckOlefinationofChloroarenesunderNonaqueousIonicLiquid(NAIL)Conditions
MW(400W)
thermalheatingR1R2t(h)yield(%)t(h)yield(%)HPh0.5953098NO2Ph0.5961095AcPh0.5931597CHOPh0.5951598BzPh0.5911593OMeCO2Bu1854086OMePh1804076MePh0.5923096CH2OH
Ph
0.5
90
30
92
Apalladium-containingsilicoaluminophosphate-31(Pd-SAPO-31)wasdevelopedbySrinivas,Ratnasamy,etal.asahighlyactivecatalystfortheHeckreactionsofaryliodidesandchlorides(Scheme31).86Thecatalystwasfoundtobemoreeffectivethanothersolid-supportedPdcatalysts(Pdoncarbon,MgO,Al2O3,orgraphite).Itworkedwellatrelativelylowtemperatures(60-120°C)andallowedcompletionofthereactionsinshorttimes(about1.5h).Pdleachedduringthereactionbutre-depositedtothesolidsupportwhenthereactionhadfinished.Thecatalystcouldberecoveredbysimplefiltrationandreusedwithoutasignificantlossofactivityorselectivityforaminimumofthreecycles.
Scheme31.HeckReactionCatalyzedbyPd-ContainingSilicoaluminophosphate-31
InanefforttocomparethereactivityofLDH-Pd(0)withthoseofotherheterogeneouscatalysts,namely,Pd/C,Pd/SiO2,resin-Pd(0),andPd/Al2O3,intheHeckolefination,correspondingexperimentswereconductedunderidentical
154ChemicalReviews,2007,Vol.107,No.1conditionswiththesamereactants.TheactivityintheHeckolefinationof4-chloroanisolewasfoundintheorder66
LDH-Pd(0)>resin-Pd(0)>Pd/C>Pd/Al2O3>
Pd/SiO2
Theseresultsindicatedthatthebasicsupport(LDH)facili-tatedtheoxidativeadditionofPd(0)with4-chloroanisoleandeventuallytheHeckolefinationreaction.
AllresultsofmechanisticexperimentsreinforcedthattheHeckolefinationof4-chloroanisoleoccursexclusivelyandwithiodobenzenepredominantlyonthesurfaceofthepalladiumnanoparticlepresumablyatdefectsites.TheplausiblemechanismproceedssimilarlytothatinthehomogeneousphaseinvolvingthePd(0)/Pd(II)cycle(Scheme32).ThenanopalladiumundergoesoxidativeadditionwithhaloarenestoaffordArPdX,asisevidentfromXPSandTGA-MSstudies.TheC1sXPSspectraoftheusedcatalystsshowextralinesaccountingfortheotherpossibleintermedi-ates.
Scheme32.PlausibleMechanismforthe
LDH-Pd(0)-CatalyzedHeckOlefinationofChloroarenes66
Thus,palladiumstabilizedonthebasicsupportLDHenablesevendeactivatedchloroarenestoundergoHeckreactions.ThebasicLDHsurfaceincreasestheelectrondensityofthePdcentertopromotetheoxidativeadditionofchlorobenzenetothePd(0),resultinginahigheractivity.Amontmorillonite-supportedPdcomplex(montmorillo-nite-ethylsilyldiphenyl-phosphine-palladium)servedasahighlyactivecatalystinHeckcouplingofaryliodideswitholefins.162,163Usingthiscatalyst,iodobenzenecoupledwithstyreneandvariousacrylatesinquantitativeyieldand95%(E)selectivity.Whenacrylonitrilewassubjectedtoarylation,adoublearylatedproduct113wasobtainedasanexceptionalcase.Itwasalsofoundthatcouplingofsubstitutediodo-benzeneswithphenylvinylacetateaffordedvariousunsym-metrical(E)-stilbenes114inhighyields(Scheme33).163Thecatalystcouldbereusedwithoutanynoticeabledeactivation.Hydroxyapatite-supportedpalladium(PdHAP-1)wasdem-onstratedasanoutstandingcatalystfortheHeckreactionofarylbromideswithstyreneorn-butylacrylate(Table46).131TherecycledPdHAP-IhadtheoriginalmonomericPd(II)
YinandLiebscherScheme33.HeckReactionsCatalyzedbyMontmorillonite-PdComplex
structureandwasrecyclablewithretentionofitshighcatalyticactivity.Pdleachinginthefiltratecouldnotbedetected.Therefore,itislikelythattheHeckreactionproceedsonthePdHAP-1surface,thatis,notwithdissolvedpalladiumspecies.ItwassuggestedthattheHeckreactiondoesnotproceedviaatraditionalPd(0)/Pd(II)cyclebutviathePd(II)/Pd(IV)mechanism.73,164,165Butthisbecameques-tionableinthelightoflaterresults.36,74,75
Table46.PdHAP-1-CatalyzedHeckReactionsofArylBromidesandOlefins
RR′t(h)yielda(%)
TONHPh249447000OMePh249045000AcPh209648000HCO2Bu209145500OMeCO2Bu249447000Ac
CO2Bu
20
98
49000
a
GCyields.
Asfurthersolid-supportedPdcatalystsusefulforHeckreactions,Pd/CaCO143,1683,139,166Pd/BaSO4,139PdonGaAs(001),167Pdongraphite,Pdonsingle-walledcarbonnanotubes(SWNT),169andPdonhydrocalcite170havetobementioned.Thelatterwasnotusefulforarylchloridesbutcouldberecycled.Interestingly,thereactionwasfasterwiththerecycledcatalystthanwiththefreshone,whichwasexplainedbyanincreaseinsurfaceareaofthecatalyst.PdCl2onsepiolitesallowedHeckcouplingofbromoben-zeneandiodobenzenewithstyrenetoberunintheabsenceofanadditionalbase.57Reusageofthecatalystwaspossible,however,withaconsiderablelossofactivity.ItissupposedthatthebasicsitesofthesupportgetblockedbythehydrohalidesformedasbyproductsintheHeckreaction.Reactivationbysteamingofthecatalystbeforereusewasadvantageous.Evidenceforheterogeneouscatalysiswasfoundbythehotfiltrationtest.
4.SonogashiraReactions4.1.PdonCarbon(Pd/C)4.1.1.InAnhydrousMediaEarlyinvestigationsofPd/C-catalyzedSonogashiracou-plingbyGuzmanandco-workers171revealedthatarylbromidescoupledwithtrimethylsilylacetylene,phenylacety-
HeterogeneousPdCatalyzedC−CCouplingReactionslene,andbutyneinthepresenceofPPh3andCuIinananhydrousmixtureoftriethylamineandacetonitrile(Table47).Remarkably,theyieldsofproductsarehigherthanthosereportedundersomehomogeneousPd(0)catalysis.ThusPd/C-PPh3-CuIhasbeendevelopedasanefficientcatalyticsystemforSonogashiracouplingreactions.Thissystemcanalsobeappliedinthesynthesisofsomeethynylpyridines(Table47,entries8,9).Interestingly,2-bromopyridine172couldbecoupledwith2-(3-hydroxy-3-methyl-but-1-ynyl)-substitutedpyridines117and118toformdipyridylethynes119and120.The2-hydroxy-2-propylgroupsaresplitoffbyGrobfragmentationunderthebasicconditions(refluxinNaOH/Et3N/MeCN)(Scheme34).
Table47.Pd/C-CatalyzedSonogashiraCouplingofArylBromideswithAcetylenes
a
Isolatedyield.
Scheme34.Pd/C-CatalyzedOne-PotSynthesisofDipyridylethynes119and120
Pd/CcatalysisisusefulfortheSonogashiracouplingofs-triazines121173andinthepyran-2-oneseries174wherechlorideorbromide,respectively,servedasleavinggroups(Tables48and49).
Aheterogeneousprotocolfortheligand-freeSonogashirareactionthatemployedPd/Casacatalystandaresin-bound
ChemicalReviews,2007,Vol.107,No.1155Table48.Pd/C-CatalyzedSonogashiraCouplingofChlorotriazines121withAlkynes173
halideR′
T(°C)t(h)yield(%)121a121aPh
65121acyclohexyl6570121an6586657540121aCMeEtOH-Bu
121asCMe-Bu110651447025121a829020121a1-OH-cyclohexyl2OH
824066121bCH822692121b
CMe2CHMeOH1-OH-cyclohexyl
2OH
82265082
4848
6290
Table49.Pd/C-CatalyzedSonogashiraCouplingof4-Bromo-6-methylpyran-2-onwithAlkynes174
yieldyieldentryR(%)entryR
(%)12n3n-Pr729954n-Bu77104-AcNH-Ph955n-Pen79114-NO356TMS-hexyl81124-Ac-Ph2-Ph7Ph
827413CH141-OH-cyclopentyl2OAc
1-OH-cyclohexyl610848
CHCH2OH902OTHP
81
51516
9-OH-9-fluorenylestradiol-17R-yl
85
tertiaryamineasbasewasparticularlyusefulforthefacileisolationofpolarnucleosidecouplingproductsobtainedfromiodonucleosideswithprotectedpropargylamines(Table50).175
Aselectivecouplingwithvariousalkyneswasachievedinthe4-positionof5-bromo-4-chloropyrimidines125(Scheme35).176TheremainingbromosubstituentcouldbeexchangedbyasecondalkynewithinasubsequentSonogashiracoupling.Position5wasattackedfirstbySonogashirareactionofcorresponding4-chloro-5-iodopyrimidines.176
4.1.2.InOrganicSolvent/WaterMixturesOrganicsolvent/watermixturesprovideagenerallyuseful,robust,andefficientmediumforPd/C-catalyzedSonogashiracouplings.K2CO3isusuallyusedinthesecases.ThusDME-waterwasusedtocouplearyliodidesandbromidesbearingeitherelectron-donatingorelectron-withdrawingsubstituents(Table51).177,178
Thismethodologycouldalsobeappliedtoheteroaromatichalidesandtriflates178,179providingexcellentyieldsofcouplingproducts127(Table52).
Itwasfurtherusedasthekeysteptosynthesizetheenantiomericallypure(S)-5-ethynyl-3-(1-methyl-2-pyrrolidi-nyl)-pyridine130(SIB-1508Y)asanovelenantiopurenicotinicacetylcholinereceptoragonist(Scheme36).178-179,180ThecouplingofN-propargylaminoacids131witharylorR-aminoheteroarylacidsbromides132,whichprovidescouldanbeeasyfurtheraccesshydrogenatedtounnaturalto133(Scheme37).181ItshouldbementionedthatnoneofthetypicalconditionsofhomogeneoussourcesofPd(0)[Pd-(PPh3)2Cl2,Pd(PPh3)4,Pd2(dba)3]weresuccessfultosynthe-sizethepyridinecross-couplingproduct132(Ar)3-py-ridyl).
156ChemicalReviews,2007,Vol.107,No.1Table50.SonogashiraCouplingofDeoxynucleosideDerivativesa
a
Standardconditions:10%Pd/C(5mol%),alkyne(2equiv),CuI(20mol%),AmberliteIRA-67(5equiv),DMF(0.1M),50°C.b
Isolatedyield.
Scheme35.Pd/C-CatalyzedSonogashiraCouplingof4-Chloropyrimidines
Table51.Pd/C-CatalyzedSonogashiraCouplingofArylHalideswithSubstitutedAlkynes
XRR′yield(%)Br3-CHOCMe2OH98Br4-NO2CMe2OH92I3-NH2CMe2OH78Br2-CNCMe2OH89Br2-CNCH2NMe2
92I4-OH1-cyclohexenyl50I
4-CO2H
1-cyclohexenyl
80
Recently,weappliedthemethodologyofPd/C-catalyzedSonogashiracouplinginaqueousmediaforthesynthesisof
YinandLiebscherTable52.SonogashiraCouplingofHeteroaromaticHalideswithSubstitutedAlkynes
Scheme36.Pd/C-CatalyzedSynthesisofSIB-1508Y
Scheme37.Pd/C-CatalyzedSynthesisofCompounds133
ω-functionalizedalkynylpyrazolo[1,5-a]pyrimidines135start-ingfrom3-iodopyrazolo[1,5-a]pyrimidines134aspotentialcalcineurininhibitors(Table53).182ItturnedoutthatPd/CwasadvantageousoverothercommonlyusedhomogeneousPd(II)orPd(0)catalysts[Pd(PPh3)2Cl2,Pd(PPh3)4,andPd-(OAc)2]inanumberofcases.
Inthecaseofapplicationof4-tosyloxybutyne(entry11),thecouplingproductwasobtainedinonly18%yieldtogetherwithitseliminationproduct3-(3-buten-1-ynyl)pyrazolo[1,5-a]pyrimidine136in36%yield(Scheme38).182
Asanefficientwaytointroduceadimethylaminopropylchainintoapyrazolering,Pd/C-catalyzedSonogashiracouplingof3-iodopyrazole137withN,N-dimethylpropargyl-aminewasused,followedbycatalytichydrogenation.183Pd/Cwasappliedinbothsteps.Remarkably,catalysiswithPd-(PPh3)2Cl2andCuIcompletelyfailed,whilePd/C,PPh3,andCuIprovidedquantitativeSonogashiracoupling(Scheme39).SimilarphenomenawereobservedbyFairlambetal.inSonogashirareactionsof4-bromo-6-methyl-2-pyrone.184
HeterogeneousPdCatalyzedC−CCouplingReactionsTable53.Pd/C-CatalyzedSonogashiraCouplingof3-Iodopyrazolo[1,5a]pyrimidines
entryR1R2R3Ryielda(%)1PhMePhCH2NMe2702HPhPhCH2NMe2913MePhPhCH2NMe2764p-Cl-PhMePh
CH2NMe2695PhMep-Cl-PhCH2NMe2546HPhPhCH2OH787PhMePhCH2OH728PhMePhCH2CH2OH719HPhPhCH2CH2OH7510MePhPhCH2CH2OH7011
Ph
Me
Ph
CH2CH2OTs
18b
a
Isolatedyield.bEnyne136(36%)wasisolated.
Scheme38.Pd/C-CatalyzedCouplingof134awith4-Tosyloxybutyne
Scheme39.Pd/C-CatalyzedSonogashiraCouplingof3-Iodopyrazole137
Couplingofhaloareneswith3-butyn-1-olinthepresenceofPd/C,PPh3,andCuIprovidedtheexpectedSonogashiracouplingproduct,whilehomogeneouscatalysisbyPdCl2-(PPh3)2/NEt3gave1-aryl-4-hydroxy-1-butanonesandderiva-tives,obviouslybyadditionalhydration.185
AsanalternativetoK2CO3,diisopropylaminecanbeusedasbaseinSonogashiracouplinginDMA-waterasreportedbyKotschyandco-workers(Table54),79buttheyieldswerenotveryhigh.ThePd/Ccatalystcouldberecoveredandreused.Afterthereaction,justminoramountsofpalladiumhadleachedfromthesupport.
Asafurthersolventsystem,waterand2-aminoethanolprovedtobeuseful.186Avarietyofterminalalkyneswerecoupledwitharyliodidesandbromidespossessingfunctionalgroupstogivethecouplingproducts141ingoodtoexcellentyields(Table55).
4.1.3.CouplingCopper-FreeandLigand-FreeSonogashiraInmostcasesofPd/C-catalyzedSonogashiracoupling,CuIandphosphineligands(PPh3)wereapplied.ButtherewerecasesreportedwhereaPd/C-catalyzedSonogashirareaction
ChemicalReviews,2007,Vol.107,No.1157Table54.Pd/C-CatalyzedSonogashiraCouplingofArylHalideswithAlkynesinDMA-Water/Diisopropylamine
Ar
Xalkyne(R)yield(%)2-pyridylBrCH2CH2OH582-pyridylBrn-Bu622-pyridylBrCMe2OH653-pyridylBrCH2CH2OH773-pyridylBrn-Bu813-pyridylBrCMe2OH693-tolylBrCH2CH2OH443-tolylBrn-Bu263-tolylBrCMe2OH484-tolylBrCH2CH2OH464-tolylBrn-Bu314-tolylBrCMe2OH512-pyridylCln-Bu542-pyridylClCMe2OH514-CN-Ph
Cl
n-Bu
0
Table55.Pd/C-CatalyzedSonogashiraReactionsinWaterand2-Aminoethanol
R1
XR2t(h)yielda(%)H
ICMe2OH9782-CH2CO2EtIPh
15934-SMeBrCMe2OH8774-MeBrCMe2OH9844-MeBrCHEtOH6774-CHOBrCHMeOH10854-CHOBrCHPhOH9594-AcBrCMe2OH9694-AcBrCH2CH2OH5.5854-Ac
Br
Ph
572CMe2OH1580bCHEtOH
15
82b
a
Isolatedyield;allreactionswerecarriedoutinwaterand2-ami-noethanol(3equiv).bAcetonitrile-H2O(1/1)wasusedassolvent.
wassuccessfulintheabsenceofphosphineligandsorevenintheabsenceofbothphosphineligandsandCuI.
Inthesynthesisof(()-tashiromine,Batesandco-workersreportedaPd/C-catalyzedSonogashiracouplingwithoutphosphineligand.187Methyl2-chloronicotinatewascoupledwith2-prop-2-ynyloxytetrahydropyrantogivethepyridylalkyne142in83%yield(Scheme40).
Scheme40.Pd/C-CatalyzedSonogashiraCouplingofMethyl2-Chloronicotinate
Ko¨hlerandco-workersreportedthePd/C-catalyzedSo-nogashiracouplingofiodobenzenewithphenylacetylenewithouttheadditionofCuIorPPh3(Table56).81Goodyieldswereachieved.Conversionsupto74%werefoundafter30minusingPdconcentrationsofonly0.125mol%(Table56,entry6;TON)592,TOF)1184).Theadditionof
158ChemicalReviews,2007,Vol.107,No.1Table56.Pd/C-CatalyzedSonogashiraCouplingofIodobenzenewithPhenylacetylene
catalystconvyieldaentry(mol%)solventbaset(h)(%)%)10.50piperidinepiperidine6776120.50pyrrolidinepyrrolidine6888030.125DMApyrrolidine61007740.125NMPpyrrolidine6968050.125DMApyrrolidine179546
0.125
DMA
pyrrolidine
0.5
74
53
a
DeterminedbyNMR.
CuIwastestedaswell.However,thisdidnotresultinhigherreactivitiesorselectivities.Largeramountsofcopperevendecreasedactivityandselectivity.
AconvenientmethodforCuI-freePd/C-catalyzedSono-gashiracouplingofarylchloridesandbromidesisbasedonaninsituhalogenexchangebyaiodidesourcesuchasanalkaliiodide,termedasHALEX-SonogashirareactionbyRothenbergetal.188Pd/CworkedbestascomparedwithPdonothersolidsupports(Al2O3,BaSO4)orhomogeneousPd-(0).ThePd/Ccatalystcouldbereusedatleastfivetimeswithoutsignificantdecreaseofyields(Scheme41).
Scheme41.Pd/C-CatalyzedCuI-FreeSonogashiraCouplingofArylChloridesandBromidesinthePresenceofKI(HALEX-SonogashiraReaction)
FurtherfacilitationofPd/C-catalyzedSonogashiracouplingispossiblebycircumventingligands,CuI,andamineandbyworkingunderanoninertatmosphere.Undertheseconditions,arangeofaromaticiodidescouldbecoupledwithaliphaticandaromaticalkynesusingcommerciallyavailable1%Pd/C(0.2mol%)ascatalyst,i-PrOH-H2O(1:1),andNa3PO4‚12H2Oasbaseat80°C(Table57).189Aryliodides
Table57.Amine-andCopper-FreeSonogashiraCouplingofArylIodideswithTerminalAlkynesCatalyzedbyPd/C
entryRR′t(h)productyielda(%)
1NO2CH2CH2OH2145a792AcCH2CH2OH5145b803OMeCH2CH2OH5145c374HCH2CH2OH5145d455NO2Ph3145e986AcPh2145f987OMePh6145g608HPh
6145h679NO22-CF3-Ph2145i9610Ac2-CF3-Ph2145j9411OMe2-CF3-Ph5145k8812H2-CF3-Ph5145l9613NO24-MeO-Ph5145m9814Ac4-MeO-Ph3145n9415OMe4-MeO-Ph6145o6016
H
4-MeO-Ph
6
145p
72
a
Isolatedyields.
YinandLiebscherbearingelectron-withdrawingsubstituents(NO2,Ac)gavealmostquantitativeyields(entries5,6,9,10,13,14),whilesomewhatloweryieldswereobtainedintheothercases.ThepotentialadvantagesofthePd/Ccatalystsystem,thatis,theeaseofseparationandfacilerecyclingofthemetalandthelowlevelofmetalcontaminationintheproduct,suggestthatacopper-,ligand-,andamine-freeSonogashiracouplingprotocolbasedontheuseofaPd/Ccatalystsystemwouldbeofmajorinterestforbothindustrialandacademicapplications.
4.2.PdonMetalOxidesAmagneticmaghemite(γ-Fe2O3)-silicananoparticle-supportedSi-PdPd-catalyst,nitrogen-seeheterocyclicalsoFigurecarbene1)wasappliedcomplex(Fe2O3-inSonogashirareactionsofaryliodidesorbromideswithphenylacetyleneprovidinghighyieldsofcouplingproducts146(Table58).110
Table58.Maghemite-Silica-Nanoparticle-SupportedPd-CatalyzedSonogashiraReactions
RXGCyield(%)
isolatedyield(%)
2-MeI94a892-MeBr94913-OMeI96883-OMeBr95934-Ac
I
96
91
a
Thefirstroundyield;thesecondtofifthroundyieldswere91%,90%,91%,and89%,respectively.
4.3.SupportsPdonMicroporousandMesoporousIn2004,DjakovitchandRolletreportedeffectivehetero-geneousSonogashirareactionsusingpalladiumzeolites[Pd-(NH3)4]2+/NH4Yundercopper-freeandligand-freeconditions(Table59).190,191OmissionofcopperisadvantageoustosuppressGlaser-typecouplingofthealkynesassidereaction.Lateron,microporous[Pd(NH3)4]2+/NaY(preparedbyimpregnationandcalcinationofzeolite)andmesoporous[Pd]-SBA-15(preparedbygraftingaphosphineligandtosilica)werepreparedandusedashighlyreactiveandselectivecatalystsincopper-freeSonogashiracouplings(Table59).58Bothcatalystsshowedexcellentstabilitytowardleaching.Thelatterwasfoundtobemorereactive.Itcouldalsobeappliedintransforminglargesubstrates(2-bromonaphtha-lene,10-bromoanthracene)becauseofitslargerporesize.Remarkably,thesecatalystsweremorereactivethanPd/CbutlessreactivethanhomogeneousPdcatalysis(Table59,footnotec).Recyclingandreuseofthecatalystwaspossiblebutwithaconsiderablelossofactivityinthefirstreuse.Sincenochangeinthestructureofthesupportcouldbedetected,thelossofreactivityisprobablyattributedtochangesofthecomplexedphosphineligand.Aryliodidesandactivatedarylbromidesgavealmostquantitativeyields(Table59).Thecatalystwasstableandrecyclable.Amor-phoussilicacouldalsoserveassolidsupportbutwaslessmuchlesseffective.58
PdonporousglasstubingprovidedhighyieldsinCu-freeSonogashirareactionsofiodo-andbromoarenesor2-bromopyridinewithalkynes.24
HeterogeneousPdCatalyzedC−CCouplingReactionsTable59.[Pd(NH3)4]2+/NH4Y-CatalyzedCopper-FreeSonogashiraReactions
[Pd(NH3)4]2+/[Pd(NH3)4]2+/
NH4YNaY
[Pd]SBA-15ArXR
yielda(%)yieldb(%)yieldb(%)Ph-I
Ph1004-MePh-IPh100(82)4-AcPh-IPh100(85)2-NO2Ph-IPh100(89)2-MePh-IPh82(67)
Ph-I
CtC-80(57)
CH2O-TMS
Ph-BrPh45c734-MePh-BrPh304-AcPh-BrPh100
2-Naphthyl-BrPh0100(99)10-Anthryl-BrPh0100(76)2H-pyran-2-one-Ph100(95)
100
4-yl-tosylate
a
GCyields;isolatedyieldsinparentheses.b
Conversion;isolatedyieldsinparentheses.cYield85%(GC)with[Pd(PPh3)2]Cl2,73%(GC)with[Pd]SBA-15,20%(GC)with[Pd(II)]/NaY,and3%(GC)withPd(0)/C.
4.4.PdonModifiedSilicaThecatalystobtainedbyencapsulationofpalladiumnanoparticlesinasilicamatrix(SiO2/TEG/Pd)showedhighcatalyticactivityintheSonogashiracouplingofmethyl4-iodobenzoatewithphenylacetylene(Scheme42).120Phos-phinesasligandswerenotnecessary.AnothertypeofPdcatalystonsilicawasobtainedwhen3-aminopropyl-modifiedsilicagelwasfunctionalizedwithphosphineligandsandtransformedintoastableimmobilizedpalladiumcomplex(Scheme36).Thiscatalystwassuccessfullyappliedinaseriesoffast,copper-freeSonogashiracouplingreactions(Scheme43).192
Scheme42.SiO2/TEG/Pd-CatalyzedSonogashiraReaction
Scheme43.ModifiedSilicaSupportedPalladiumCatalyzedCopper-FreeSonogashiraCoupling
4.5.PdonClayandOtherInorganicMaterialsLayereddoublehydroxidesupportedpalladiumnanopar-ticles(LDH-Pd(0))allowedSonogashiracouplingofchlo-roarenestobecarriedoutunderCu-freeconditions(THF/water,NEt3)andprovidedhighactivity(Table60)66Evenelectron-richchloroarenescouldbecoupledinthisway(Table60,entry2).Thecatalyst(1mol%)wasusedinfive
ChemicalReviews,2007,Vol.107,No.1159cyclesandshowedconsistentactivityinthecouplingofphenylacetyleneandchlorobenzene.Nonaqueousionicliq-uids(NAIL)couldalsobeusedforthiscatalyticsystem(Table60,entry1).
Table60.LDH-Pd(0)-CatalyzedSonogashiraReactionofChloroareneswithPhenylacetylene
a
UnderNAILconditions.
5.Stille,Fukuyama,andNegishiReactions5.1.StilleReactions5.1.1.PdonCarbon(Pd/C)Liebeskindandco-workers193,194reportedPd/C-catalyzedStillecross-couplingreactions.TheprotocolwasoptimizedbytheadditionofCuIascocatalystandtheligandAsPh3[Pd/C(0.5mol%),CuI(10mol%),AsPh3(20mol%)]toallowthereactiontooccuratareasonableratewithavarietyofsubstrates.BesidestheadvantageofusingastableformofPd(0),theyieldsoftheproductsundertheseconditionswerebetterthanthoseobtainedusingPd2(dba)3asthesourceofPd(0)(Table61).Theuseofvinylhalidesandtriflatesaswellasarylhalideswaswelltolerated.However,arylfluorosulfonatesandaryltriflatesperformedpoorlyundertheseconditions(20-30%conversion)duetocompetingtriflatehydrolysis.
Asanalternativetohalidesorsulfonates,hypervalentiodoniumsaltswereusedinPd/C-catalyzedStillecouplingsasreportedbyKangandco-workers.Thereactioncanconvenientlybecarriedoutatroomtemperatureinaqueousacetonitrile(Table62).195
5.1.2.PalladiumonKF/Al2O3SolventlessStillereactionsonpalladium-dopedKF/Al2O3wereinvestigatedundermicrowaveirradiation(Scheme44).108
5.1.3.PdonModifiedSilica(SiO2/TEG/Pd)ThecatalystSiO2/TEG/Pdconsistingofpalladiumnano-particlesencapsulatedinasilicamatrixshowedhighcatalyticactivityintheStillecouplingofaryliodideswithallyltribu-tylstannane(Scheme45).120
5.2.FukuyamaReactions5.2.1.PdonCarbon(Pd/C)CouplingoforganozincreagentswiththiolesterstoketonescanbecatalyzedbyPd/C.Thismethodologywasappliedtothealiphaticorganozinccompound159bySekiandco-workers196representingthefirstexampleofcouplingofsp3-hybridizedorganometallicsinthepresenceofhetero-
160ChemicalReviews,2007,Vol.107,No.1Table61.Pd/C-CatalyzedStilleCross-Coupling193
a
Isolatedyieldofpureproduct.b5mol%Pdwasused.cReference194,95°C.
Table62.Pd/C-CatalyzedCouplingofOrganostannaneswithHypervalentIodoniumSalts
geneousPd/C(Scheme46).Itisworthmentioningthatnopoisoningofthecatalystoccurredbythereleasedthiol.The
YinandLiebscherScheme44.SolventlessStilleReactionsbyPalladium-DopedKF/Al2O3
Scheme45.SiO2/TEG/Pd-CatalyzedStilleReaction
Scheme46.Pd/C-CatalyzedFukuyamaReactionsinVariousSolvents
additionofapolaraproticsolventsuchasDMA,NMP,orDMF(4%v/v)improvedtheyieldconsiderably,probablybecauseofdeaggregationoftheorganozinccompound.TheseoptimizedconditionswereappliedtotheFukuyamareactionofaseriesofotherthiolesters161(Table63).
Table63.Pd/C-CatalyzedFukuyamaCouplingReactions
Ryield(%)CH3(CH2)6913-thienyl673-Cl-Ph
90EtO2C(CH2)6764-EtO2C-Ph70PhCO(CH2)2
74
ThePd/C-catalyzedFukuyamareactioncouldalsobeefficientlyusedinthesynthesisofthedehydrobiotinderiva-tive164(Scheme47).Pd/CturnedouttobeadvantageousoverhomogeneousPdcatalysts.196
Scheme47.SynthesisoftheDehydrobiotinDerivative164
5.2.2.Pd(OH)2onCarbon(Perlman’sCatalyst)AsalsofoundinSonogashiraandSuzukicouplings,Pd-(OH)2/Ccatalyst(Pearlman’scatalyst)wasfoundtobesuperiortoPd/CinFukuyamacouplingofthiolesterswiththeorganozincreagent159(Table64)affordingmuchhigheryields.197-199ThebetterperformanceofPd(OH)2/CwasexplainedbybetterleachingofPd(0)formedbyreductionbytheorganozinccompound.
5.3.Pd/C-CatalyzedNegishiReactionsRossiandco-workersreportedthePd/C-catalyzedcross-couplingofarylzincchlorideswith-haloacrylatesand
HeterogeneousPdCatalyzedC−CCouplingReactionsTable64.FukuyamaCouplingReactioninthePresenceofPd(OH)2/C
yielda(%)
PdcatalystR(mol%)T(h)Pd(OH)2/C
Pd/C4-MeOPh(CH2)20.15508430CH3(CH2)60.6249352cyclohexyl0.6727941EtO2C(CH2)60.9177867PhCO(CH2)20.9237050Ph
0.97172393-Cl-Ph0.62573253-thienyl
0.9
68
61
19
a
Isolatedyield.
cinnamates167.200AsPh3wassuperiortoPPh3asligand(Table65),andthe-halidewasattackedselectively.
Table65.Pd/C-CatalyzedNegishiReactions
a
Isolatedyield.Inentry1,PPh3wasused;inentries2-5,AsPh3wasused.
6.Ullmann-TypeCouplingReactionsTheUllmann-typereaction,thatis,homocouplingofarylorvinylhalidesisconventionallymediatedbycopperathightemperatures.Inrecentyears,Pd/C-catalyzedUllmann-typecouplinginthepresenceofreducingreagents,suchassodiumformate,hydrogen,zinc,indium,ortriethylaminehasat-tractedincreasingattention.
6.1.Pd/C-CatalyzedAryl−ArylCouplingAsfoundbyBamfieldandco-workers201in1978,biaryls169canbeobtainedinmodestyieldsfromchloro-orbromoarenesinthepresenceofPd/Candasurfactantinaqueousalkalinesodiumformateasareducingagent(Scheme48).
KineticsandmechanismofthereactionwasinvestigatedbySassonetal.suggestingasingleelectrontransfer(SET)processfromPd(0)tothechloroareneformingchloroareneradicalanions.202Workinginatwo-phasesystemunderphase-transfercatalysisconditionshelpedtoincreasetheyield(Scheme49).203ThePd/Ccatalystwasrecycledwithout
ChemicalReviews,2007,Vol.107,No.1161Scheme48.Pd/C-CatalyzedAryl-ArylCouplinginthePresenceofaSurfactantandHCO2Na
losingitscatalyticactivitysimplybyfiltrationandwashingwithmethanol.
Scheme49.Pd/C-CatalyzedHomocouplingofChlorobenzene
Excellentyieldsofbiaryls169wereachievedinanoil-in-watermicroemulsion.203,204Theseresultsdemonstratethatmanyindustriallyimportantsubstitutedbiarylsmaybeamenabletosynthesisinveryhighyieldsbysimplymodifyingthesolventassemblage(Table66).204
Table66.Ullmann-TypeCouplingofHaloarenesinMicroemulsionaselect.select.
microemulsiontconv(%)(%)entrywater/oilhaloarene
(h)
(%)Ar-ArAr-H1O/WPhCl3.51009282O/WPhBr3.51009463O/WPhI3.51009824O/W4-Me-Ph-Cl68389115O/W4-CHO-Ph-Cl5929286bO/WPhCl229253477W/OPhCl5.510031698
nonecPhCl4
100
54
46
a
Reactionconditions:haloaryl(0.013mol);5%Pd/C(1g);TBAB
(1g);sodiumformate(1.5g);NaOH(1.5g);75°C.bNoTBABwasused.cWaterwasusedassolvent.
HydrogenwasusedasreducingreagentinPd/C-catalyzedUllmann-typecouplingofvariouschlorobenzenesandbro-mobenzenetobiaryls169inthepresenceofaqueoussodiumhydroxideandasmallamountofPEG-400(Table67).205Arenes171formedbysimplereductionofthehalobenzeneswereobservedasbyproductstovariousextents.ThePd/Ccatalystcouldberecycledsimplybyfiltrationandwashingwithwaterandmethanol.Aftersevenruns,thecatalystretained>99%ofitsactivity.
ZinccouldalsobeusedasreducingreagentinPd/C-catalyzedaryl-arylcouplingofhaloarenesinaqueoussodiumhydroxideinthepresenceofPEG-400,206inaqueousacetonewithoutanadditionalbaseundermildconvenientconditions(air,RT),207orinwaterinthepresenceofcrownethers.208Althoughhighyieldswereachieved,onlyiodo-andbromoarenescouldbeusedinthelattermethod(Table68).207
Incontrast,Pd/C-catalyzedzinc-mediatedUllmann-typecouplingcouldbeimplementedwithavarietyofhalidesincludingchlorobenzeneswhenthereactionwascarriedoutundercarbondioxide(Table69).209,210
IndiumasreducingagentinPd/C-catalyzedaryl-arylcouplingofarylandpyridyliodidesprovidedhighyields.ShortreactiontimesweresufficientwithDMFassolventandLiClasadditive(Table70).211Aldehyde,keto,andthioethergroupsweretoleratedinthearyliodidecomponents.
162ChemicalReviews,2007,Vol.107,No.1Table67.Pd/C-CatalyzedAryl-ArylCouplinginthePresenceofHydrogen
a
YieldsbasedonGC.bIsolatedyieldsinparenthesis.
TriethylaminewasalsousedasreducingreagentinPd/C-catalyzedUllmann-typecoupling.ExcellentyieldswereachievedwithN,N-bis(4-fluorophenethyl)-5-iodoisophthal-amide(Scheme50).212Themethodologywasappliedtothecombinatorialsynthesisofbiaryllibraries.
6.2.HalidesPd/C-CatalyzedHomocouplingofVinylForPd/C-catalyzedhomocouplingsofvinylhalides,in-diumwasusedasreducingreagent.211Excellentregioselec-tivitiesandhighyieldsofthebivinylproducts178wereobtainedinDMFinthepresenceofLiCl(Table71).p-Bromo-R-bromostyreneselectivelyafforded2,3-di(p-bro-mophenyl)-1,3-butadienein88%yield(entry9)implyingthatavinylbromidemoietyismorereactivethanarylbromideinthiscouplingreaction.(E)-Bromostyrenepro-duced(E,E)-1,4-diphenyl-1,3-butadienein91%yieldac-cordingly(entry11).
6.3.ArylPd/C-CatalyzedandVinylHalidesIntramolecularCouplingofIndiumisalsousefulasareducingreagentinintra-molecularPd/C-catalyzedUllmann-typecouplingreactionsaffordingcarbocyclesandheterocycles.211Thetworeactivemoietiescanbearyl-aryl,aryl-vinyl,andvinyl-vinyl(Table72).
7.andHomocouplingAlkynesofArylboronicAcids,Pyridines,7.1.AcidsPd/C-Catalyzed(Suzuki-TypeHomocouplingHomocoupling)ofArylboronicIn1996,amechanisticstudyaboutPd-catalyzedSuzuki-typehomocouplingofarylboronicacidsrevealed213thatlowtomoderateyieldsofsymmetricalbiarylswereformedfromarylboronicacidswhenPd(PPh3)4orPd(OAc)2wasusedascatalyst.Anefficienthighyieldingapproachtothehomo-
YinandLiebscherTable68.Zn-MediatedUllmann-TypeCouplingofArylHalidesCatalyzedbyPd/C
a
DeterminedbyGC/MSanalysis.
couplingofarylboronicacidwasfoundlateronbyKozaandCaritabasedontheadditionofcoppernitratetoenhancethecouplingrate.214
In2005,Cravottoetal.reportedaheterogeneousPd/C-catalyzedSuzuki-typehomocouplingofarylboronicacid.High-intensityultrasound(US)ormicrowave(MW),aloneorcombined,promotedthisreaction.105,215Theseligand-freecouplingswerecarriedoutinaqueousmediaandaffordedthecorrespondingbiaryls185inacceptabletogoodyields(Table73).105
7.2.Pd/C-CatalyzedHomocouplingofPyridines4,4′-Dialkyl-2,2′-bipyridines187and2,2′:6′,2′′-terpy-ridines188arewidelyusedaschelatingagents.Transitionmetalcomplexesofthesecompoundsareveryimportantduetotheirchemicalreactivityandphotochemicalproper-ties.216,217
Thereareseveralmethodstopreparecompounds187and188,amongthem,aone-stepsynthesisviaPd/C-catalyzed
HeterogeneousPdCatalyzedC−CCouplingReactionsTable69.Pd/C-CatalyzedUllmann-TypeCouplingofArylHalidesinthePresenceofCO2210
entryAr-Xta(h)yieldb(%)1c2dPh-I273Ph-I154ePh-I15>41995Ph-I
86564-Me-Ph-I9572-Me-Ph-I1588784-MeO-Ph-I244-CF15971091-Naph-I3-Ph-I481009511Ph-Br
24124-MeO-Ph-Br152491134-Me489514f2,6-di-MeO-Ph-Br2N-Ph-Br7285152-OH-1-Naph-Br487816gPh-Cl368117gPh-Cl
365618g3,5-di-MeO-Ph-Cl489619g
1-Naph-Cl3-EtO36812C-Ph-Cl
96
9593
a
Reactionconditions:ArX(2mmol);5%w/wPd/C(300mg);Zn(170mg);H2O(5mL);CO2(1.0MPa).bIsolatedyields.cIntheabsenceofCO2.dCO2,1atm,bubbling.eCO2,6.0MPa.f2-Naphtholwasobtainedin17%yield.g5%Pd/C(400mg).
Table70.Ullmann-TypeCouplingReactionsofArylHalideswithPd/CandIn
biarylproduct174t(h)yielda(%)
(1-Naph)(4-22.5(4-MeO-Ph)n-Bu-Ph)22.587(3-MeO-Ph)22.585(4-HO-Ph)22.591(4-EtO22.586(3-EtO2C-Ph)2287(4-F2C-Ph)22.588(2-F3C-Ph)2286(4-CHO-Ph)3C-Ph)22.592(4-Ac-Ph)238587(4-Cl-Ph)22.5(2-thienyl)2288(2-Py)21.591(3-Py)21.5922
3
8689
a
Isolatedyield.
Scheme50.Pd/C-CatalyzedHomocouplingofArylIodide175inthePresenceofEt3N
dehydrogenativehomocouplingofpyridines.Thisisthesimplestandmostefficientmethod.Intheearly1960s,Pd/Cwasextensivelyappliedasacatalysttosynthesizebipyridinebyoxidativecouplingofpyridineintheabsenceofbaseoradditives.218-220In1971,aseriesof2,2′-bipyridines187and2,2′:6′,2′′-terpyridines188werepreparedbyrefluxingalkyl-pyridines186inthepresenceof5%Pd/Ccatalyst(Table74).221
ChemicalReviews,2007,Vol.107,No.1163Table71.SynthesisofButadienesbyPd/C-CatalyzedCouplingofVinylHalides
entryR1R2yielda(%)
12nPh-HexH9234Ph
H9354-MeO-PhH63-NHH8973-HO-Ph2-PhH8782-Cl-PhH794-FH721094-Br-Ph3C-PhH89114-PyH88H
H88Ph
8991
a
Isolatedyield.
Table72.IntramolecularVinylandArylCouplingReactionsa
a
Reactionperformedinthepresenceof2.5mol%ofPd/C,50mol%Inand1.5equivofLiClinDMF(0.5M)at100°C.bIsolatedyield.c
0.05MLiClinDMFwasused.
Table73.Pd/C-CatalyzedSuzuki-TypeHomocouplingofArylboronicAcids
a
Isolatedyield.
Inrecentyears,thePd/C-catalyzeddehydrogenativecouplingofpyridineswaswidelyappliedtothesynthesis
164ChemicalReviews,2007,Vol.107,No.1Table74.Pd/C-CatalyzedSynthesisof4,4′-Dialkyl-2,2′-bipyridines187and
4,4′4′′-Trialkyl-2,2′:6′,2′′-terpyridines188a
bipyridine187terpyridine188pyridine(R)yieldb(%)yieldb(%)Me10-15(15-25)1-2(1.5-3)Et17-25(20-25)3-5(2-3)i-Pr40-50(20-30)12-15(5-8)n-Pen
13-20(15-20)
3-5(2-3)
aReactionconditions:5%Pd/C(1g);4-alkylpyridine(25mL).b
Isolatedyieldsachievedbyundegassedcatalyst;inparenthesisyieldswithdegassedcatalyst
of4,4′-dimethyl-2,2′-bipyridines,222-2244,4′-di-(3-pentyl-2,2′-bipyridines),2254,4′-di-(5-nonyl-2,2′-bipyridines),2264,4′,5,5′-tetramethyl-2,2′-bipyridines,227anddiethyl2,2′-bipyridine-5,5-dicarboxylate.228When4-ethylpyridinewasrefluxedwith10%Pd/Cfor9days,4,4′,4′′-triethyl-2,2′:6′,2′′-terpyridine(Et3tPy)wasisolatedin20%yield.229Thesebipyridinesandterpyridineswerefurtherusedinpreparationoftransitionmetalcomplexesandotherfunctionalizedcompounds.
7.3.(Glaser-TypePd/C-CatalyzedCoupling)HomocouplingofAlkynesTheoxidativecouplingofterminalacetyleneshasbeenextensivelyinvestigatedandreviewed.230-232TheGlasercouplingreaction,i.e.,thecopper-mediatedoxidativehomocoupling,233-236istheclassicmethod.Thismethodisstillwidelyusedinmodernorganicsynthesis.237-239
However,therearesomereportsaboutthePd-catalyzedhomocouplingofalkynes(Glaser-typecoupling)underhomogeneouscatalyticconditionsusingI2,240chloro-acetone,241,242orethylbromoacetate243asoxidant.FairlambreportedthehomocouplingofalkynescatalyzedbyPd-(PPh3)2Cl2/CuIwithouttheadditionofanoxidant.244Het-erogeneousPd/C-catalyzedhomocouplingof(3-aminophenyl)-ethynewasfirstreportedbyus(Scheme51).WeattemptedtheSonogashiracouplingof3-iodo-5,7-diphenylpyrazolo-[1,5-a]pyrimidine190with(3-aminophenyl)ethyne189underPd/C-CuI-PPh3catalysis.NoSonogashiracouplingproductwasfound,butthehomocouplingproduct191wasisolatedinquantitativeyield.182,245Runningthereactionwithout190gavetheproduct191onlyin74%yield.245
Scheme51.Pd/C-CatalyzedHomocouplingof(3-Aminophenyl)ethyne189
Straussetal.demonstratedthatPdonporousglassinthepresenceofaircanbeusedforaGlaser-typecouplingofphenylethyne.24
YinandLiebscher8.OtherCouplingReactions8.1.CyanationofArylBromidesTheutilizationofhomogeneousPdcatalystsinthecyanationofarylhalideshasarousedconsiderableattentioninrecentyears.246Inordertomakethisreactionmoreattractivetoindustrialapplication,heterogeneousPd/C-catalyzedcyanationwasapproached.Hatsudaetal.reportedapracticalhigh-yieldingsynthesisofarylnitriles192byPd/C-catalyzedcyanationofarylbromidewithZn(CN)2inthepresenceofPPh3andZnBr2.247,248Functionalgroupssuchasacetyl,hydroxy,amino,andsulfidewereallcompatiblewiththereactionconditions(Table75).
Table75.Pd/C-CatalyzedCyanationofArylBromides
a
DeterminedbyHPLC;Pd/C(4mol%),PPh3(0.16equiv),Zndust(0.4equiv),Br2(0.2equiv),andZn(CN)2(0.6equiv)wereused.bPd/C(8mol%),PPh3(0.32equiv),Zndust(1.2equiv),Br2(0.4equiv),andZn(CN)2(0.5equiv)wereused.
8.2.CarbonylationsCarbonmonoxideisanotheroptiontointroduceaC-1unitintoasubstratebysolid-supportedPd-catalysis.Pd/CwasusedinthepresenceofPPh3/TsOH/LiCltosynthesize2-arylpropionicacids196bycarbonylationof1-aryl-1-chloroethanes193(Scheme52).249Thecatalystsystemwasalsoapplicabletothecarbonylationofvarious1-arylethanols194andtheircorrespondingolefins195(Scheme52),as
Scheme52.Pd/C-CatalyzedSynthesisof2-ArylpropionicAcids196
HeterogeneousPdCatalyzedC−CCouplingReactionsdemonstratedinTable76.Inallcases,highconversions,selectivities,andTOFwereachieved.
Table76.Synthesisof2-ArylpropionicAcids196byPd/C-CatalyzedCarbonylationssubstratet(h)conv(%)select.(%)TOF(h-1)193a4.29699.23375194a49299.13400195a49099.33300193b1390981010194b4.692982900193c
24
90
99
552
Esters197wereobtained,whenthePd/C-catalyzedcarbonylation62wascarriedoutinthepresenceofalcohols(Scheme53).
Scheme53.Pd/C-CatalyzedAlkoxycarbonylation
Asanalternative,estersandalsoanilidescouldbesynthesizedbyPd-catalyzedcarbonylationofaryliodidesoractivatedarylbromidesinthepresenceofbutanoloraniline,respectively,usingasilica-supportedbidentatearsinepalladiumcomplex“Si”-2As-Pd(II)underatmosphericconditions(Scheme54).250Thecatalystshowedhighactivityandcouldberecoveredandreused.
Scheme54.CarbonylationsbySilica-SupportedBidentateArsinePalladiumComplex
8.3.r-ArylationsofDiethylMalonateThehomogeneouspalladium-catalyzedarylationofcar-bonylcompoundsusingarylhalideshasbecomeausefulandgeneralsyntheticmethod.251-254Thereactioncouldalsobecatalyzedinheterogeneousfashionwithdiethylmalonateasthecarbonylcompound.255Forarylbromides200,Pd-exchangedNaYzeolites([(Pd(0)],[(Pd(II)],andentrapped[(Pd(NH3)4])exhibitedgoodactivityatlowPdconcentrations(2mol%)(Table77).Thecatalystscouldeasilybeseparatedandreusedwithoutareallossinactivity(entries1-4).
8.4.ArylationsofAromaticCompoundsPd-catalyzedarylationreactionsofarenesbyhaloarenestobiarylproductsweresuccessfullyappliedinintermolecularfashiontoavarietyofheterocyclicarenes256-258andarenespossessingadirectinggroup.259-261Inanintramolecularfashion,five-andsix-memberedringswereformed.262-265Inthesecouplings,hydrogenhalideiseliminated.Palladiumhydroxideoncarbon(Pearlman’scatalyst)effectivelycata-
ChemicalReviews,2007,Vol.107,No.1165Table77.Pd/Zeolite-Catalyzedr-ArylationsofDiethylMalonatea
GLCisolatedentrycatalystRyield(%)yield(%)12Pd(0)Pd(II)-Me3Me31(33)b21Me4141(38)b(39)b324Pd(OAc)-NaYNaYMe51(49)b295Pd(NH2-NaY3)4-NaYOMe5738456Pd(NHH47417Pd(NH3)4-NaY3)4-NaYF64508Pd(NHPd(NH3)4-NaY9
3)Ac7060)4-NaYPd(NH34-NaY
NO2
98
84
a
Reactionconditions:15mmolofarylbromide,10mmolofdiethylmalonate,20mmolofbase,2mol%Pd-catalyst,6mLsolvent,110°C,20h.bYieldofsecondruninparentheses.
lyzesarylationreactionsofaryliodidesandbromides,providingexcellentarylation-to-hydrodehalogenationratios(>30:1)withabroadscopeforbothintra-(Table78)andintermoleculararylationprocesses(Table79).29,266Thestudiesindicatedthatanactivehomogeneouspalladiumspeciesisproducedunderthereactionconditions.
Table78.ScopeofIntramolecularDirectArylationReactionsa
a
Conditions:substrate,KOAc(2equiv),andPd(OH)2/C(10mol%)addedtoascrewcapvialfollowedbyDMA(0.2M)andheatingto140°Cfor12-24h.bIsolatedyield.c20%ofhydrodebrominatedproductwasalsoobtained.
166ChemicalReviews,2007,Vol.107,No.1Table79.IntermolecularArylationsa
a
Conditions:substrate,KOAc(2equiv),andPd(OH)2/C(10mol%)addedtoascrewcapvialfollowedbyDMA(0.2M)andheatingto140°Cfor12-24h.bIsolatedyield.cIsolatedasa12:1mixtureofthe2,5/2,3isomers.dMesoporous[Pd]/SBA-15wasused;NMP,NaOAc,140°C,12d.29
8.5.AllylationsSeveralsolidsupportscanbeusedinPd-catalyzedallylicsubstitutions.Alreadyin1983,BergbreiterandChenreportedthefirstPd/C-catalyzedallylicsubstitutionofallylacetatebydiethylamineinthepresenceoftriphenylphosphine.267Thecatalystusedinthereactionwasreadilyrecyclableatleast10times.
Usingtriphenylphosphineastheligand,FelpinandLandaisreportedapracticalPd/C-mediatedallylicsubstitutioninwater(forsomeexamples,seeScheme55).268Allylacetates206,207,and208coupledwith2,2-dimethyl-[1,3]-dioxane-4,6-dione209affordingbiallyl-substitutedproducts210and211.Underthesameconditions,208coupledwithmalonicaciddiethylester200toprovidemonoallyl-substitutedproduct212.
Scheme55.Pd/C-CatalyzedAllylationsofMalonates
PalladiumonorinKF-Al2O3wasusedasaneffectivecatalystinligandlessandsolvent-freeallylicsubstitutions
YinandLiebscherundermicrowaveirradiation(Scheme56).108Thecatalystsystemwaspreparedbygrinding[Pd2(dba)3]togetherwithKF-Al2O3.Severalacidiccarbonylcompoundswereusedasnucleophile.Monoallylationproducts215and216ordiallylationproduct217couldbeachieved.Mixturesofregioisomericproducts218and219wereobservedwiththesubstitutedallylacetate206.
Scheme56.Pd/KF-Al2O3-CatalyzedAllylationsunderMWIrradiation
Allylationofmalonatecouldbeachievedinhighlyenantioselectivefashionandhighyieldwhen[Pd[η3C3H5)-Cl]2supportedbyreversephasesilicawasmodifiedbythechiralphosphine-oxazolineligandL(Scheme57).160
Scheme57.EnantioselectiveAllylationofMalonate
Allylationsofthelessacidicacetaldehydeoracetonewithallylicchloridescouldbeimplementedusingamodifiedsilica-supportedpalladiumcomplex“Si”-As-Pd(0),whereanarsineactsasligand.SinceSnCl2wasusedasanadditionalreducingagent,homoallylicalcoholswereob-tainedasproducts(Scheme58).269Thecatalystcouldberecoveredandreused.
Scheme58.CarbonylAllylationsunderReductiveConditionsCatalyzedby“Si”-As-Pd(0)
8.6.IntermolecularHeck-TypeCouplingLautensandco-workersreportedaPd/C-catalyzedligand-freeintermolecularHeck-typecouplingofaryliodideswith
HeterogeneousPdCatalyzedC−CCouplingReactionsallylacetates.UnlikeinagenuineHeckreactionwherehydrideiseliminatedaftertheoxidativeaddition,acetateservesasleavinggroupinthiscase(Table80).270Substratesbearingelectron-donatinggroupsrequiredlongerreactiontimes(entry5).However,substrateswithstronglyelectron-withdrawingsubstituentsledtorapidisomerizationofthealkenestothethermodynamicallymorestablestyrylsystem(entries6and8).Bothchloroandbromosubstituents(entries2and3)weretoleratedunderthereactionconditions.270
Table80.Heck-TypeCouplingofAllylAcetatewithVariousArylIodides
a
Isolatedyields.b5%Pd/Cwasused;18%ofinternalolefinwasobserved.
Apossiblemechanism(Scheme59)forthisreactioninvolvesinitialoxidativeadditiontoPd(0)followedbycarbopalladationoftheolefin.Subsequent-acetoxyelimi-nationgivesthefinalallylproduct.ReductionoftheresultingPd(II)toPd(0)ismostlikelyachievedbycoordinationofanaminebasefollowedby-hydridetransferandreductiveeliminationofhydrogeniodide.
9.PdonSolidSupportinTandemReactionsSolid-supportedPd-catalyzedcouplingreactionsbyC-C-bondformation,suchasSonogashiraorHeckreaction,can
ChemicalReviews,2007,Vol.107,No.1167Scheme59.ProposedMechanismfortheHeck-TypeCoupling
befollowedbyfurtheradditionreactions.Inthisway,heterocyclescanbeformedundercyclization.
9.1.SonogashiraCouplinginTandemReactionsWheno-aminoaryliodidesaresubmittedtoSonogashirareactions,intramolecularadditionoftheaminogrouptotheC-Ctriplebondcanleadtotheformationofindoles.Asonepossibility,Pd/C-CuIcouldbeusedascatalyst(Scheme60).271Theintermediatecompound225resultingfromtheSonogashiraC-Ccouplingreactionbetween2-iodoanilineandphenylacetylenewasneverobservedintheseexperi-ments.Thisindicatesthattheheteroannulationisrapidunderthereactionconditions.
Scheme60.Pd/C-CatalyzedSynthesisof2-Phenylindolea
a
Reactionconditions:5mmolof2-iodoaniline,5mmolofphenylacety-lene,15mmolofEt3N,1mol%Pd/C,1mol%CuI,15mLofDMF/H2O(1:1),120°C,6h.
Palandco-workersreportedageneralone-potsynthesisof2-alkyl/aryl-substitutedindoles228viaPd/C-mediatedcoupling/5-endo-digcyclizationofterminalalkyneswitho-iodo-N-mesylanilines227inwater.272ThereactionwascarriedoutusingPPh3andCuIascocatalystand2-amino-ethanolasabase(3equiv).Thereactionappearedtotolerateavarietyoffunctionalgroupspresentinthealkynesanddidnotrequiretheuseofanyorganiccosolvent(Table81).AgreatervarietyofN-substituentsatthe2-iodoanilineswaspossiblewhenPd-NaYwasusedascatalyst(Table82).273Cucatalysiswasnotnecessary.Itwasfoundthattheproductformationlargelydependedonthesolvent,base,andreactiontemperature.Therecycledcatalystshowedgoodreusabilityinthisheteroannulationreaction.
[Pd(NH3)4]2+/(NH4)Yascatalystsallowedimplementationofthesynthesisof2-phenylindolestartingfromo-iodoanilineandphenylacetyleneunderCu-freeconditionsin72%yield(Table83).191Similarly,microporous[Pd(NH3)4]2+/NaYormesoporous[Pd]/SBA-15silicacouldbeusedforthesynthesesofaseriesof2-substitutedindoles.29
Wheno-iodophenolsweresubmittedtoSonogashiracouplingwithalkynesthesubsequentintramolecularcy-clizationledtobenzo[b]furans.Becauseofitsrelevancetonaturalproductsandtopharmacymany2-substitutedbenzo-[b]furanderivativeswerepreparedinthiswayduringthelastyearsusingahomogeneouspalladiumcatalystandcopperiodideascocatalystundermildconditions.274-277Asaheterogeneousalternative,Pd/Cwasappliedinthepresence
168ChemicalReviews,2007,Vol.107,No.1Table81.Pd/C-CatalyzedSynthesisof2-SubstitutedN-Methylsulphonyl-5-methylindoles
a
Isolatedyields.
Table82.SynthesisofIndolesCatalyzedbyPd-NaYa
a
Reactionconditions:0.5mmolofarylhalide,1.0mmolofalkyne,5mol%Pd-cat.,0.5mmolofLiCl,1.0mmolofCs2CO3,10mLofDMF,at140°Cfor6h.bIsolatedyield.
ofCuI,PPh3,andprolinol.278
Thismethodtoleratedavarietyoffunctionalgroupsinthealkynes,aswellasabaselabilenitrogroupintheo-iodophenols(Table84).Theprotocoldoesnotrequiretheuseofphasetransfercatalystorwater-solublephosphineligandsandisfreefromtheuseofanyorganiccosolvent.
Pd(NH3)42+/(NH3)Yasazeolite-supportedversionallowedimplementationofacopper-freecouplingofo-iodophenolor2-iodo-4-nitrophenolwithphenylacetylene(Scheme61).191Isocoumarins235couldbesynthesizedbySonogashiratandemreactionswheno-iodobenzoicacids234were
YinandLiebscherTable83.Cu-FreeSynthesisofIndolesCatalyzedby
Microporous[Pd(NH3)4]2+/NaYorMesoporous[Pd]/SBA-15Silicaa
a
Reactionconditions:5mmolofarylhalide,7mmolofalkyne,1mol%Pdcatalyst,8mmolofNEt30.5mmolofLiCl,1.0mmolofCs2CO3,10mLofDMF,at140°Cfor6h.bGCyield;isolatedyieldinparenthesis.c75%GCyieldwithPd(OAc)2.Table84.Pd/C-CatalyzedSynthesisof2-SubstitutedBenzo[b]furans
a
Isolatedyield.
coupledwithterminalalkynes.Tenyearsafterthehomo-geneousversion,279Paletal.foundaPd/C-mediatedsynthesisofisocoumarinsin2005(Table85).280ThecatalystwasusedinthepresenceofEt3N,PPh3,andCuI.
9.2.HeckCouplinginTandemReactionsPd/C-catalyzedHeckcouplingreactionscouldbecom-binedwithhydrogenationusingthesamecatalyticsystem.
HeterogeneousPdCatalyzedC−CCouplingReactionsScheme61.Pd(NH3)42+/(NH3)Y-CatalyzedSynthesisof2-Phenylbenzo[b]furans
Table85.Pd/C-CatalyzedSynthesisof3-SubstitutedIsocoumarinsa
a
Allreactionswerecarriedoutusingiodide(1.0equiv),alkyne(2.0equiv),Et3N(5.0equiv),anda1/4/2ratioof10%Pd/C(3mol%),PPh3,andCuI,inEtOHfor16h.bIsolatedyields.
Inthisway,1,2-diphenylethanes236and237wereobtainedfromstyreneandbromobenzeneoro-bromonitrobenzene,respectively(Scheme62).271
Scheme62.One-PotSynthesisof1,2-Diphenylethanes236and237
Pd/C-catalyzedHeckcouplingwasfurthercombinedwithsubsequentSuzukicouplinginordertosynthesize4-styryl-biphenyl240,asubstructureofpharmaceuticallyactive
ChemicalReviews,2007,Vol.107,No.1169compounds.271BecauseHeckcouplingismoreselectivefordifferentleavinggroupsthanSuzukicoupling,theHeckcouplingwasappliedasthefirstreactionstepandSuzukicouplingasthesecond(Scheme63).
Scheme63.Pd/C-CatalyzedOne-PotSynthesisof4-Styrylbiphenyl240
10.ConclusionsandPerspectivesNowadays,Pd-catalyzedhomogeneouscouplingreactionsbelonginthetoolboxofeachsyntheticorganicchemistandhavebeenusedinmanyfieldsoforganicsynthesisleadingtoproductsofvariousinterests.However,industrialapplica-tionsofthesereactionsarestillchallengingbecausethecatalystsareexpensive,cannotberecycled,andaredifficulttoremovefromtheproduct.Thelatterfactisadrawbackinparticularforpharmaceuticalindustries.
AlthoughPdfixedoninorganicandorganicsupportshavebeenknownforalongtimeandappliedtoC-Ccouplingreactionsinsinglecasesmorethan30yearsago,theirversatilityhasonlyrecentlybeenshowninalmostalltypesofC-Ccouplingsduringthelastdecades.Thismethodologyhasnotbeenappreciatedbymanyorganicchemistssofar.Inmostcases,theirfirstchoiceishomogeneousPdcatalysts.Theheterogeneousmethodologyoffersanumberofadvantagessuchashighstabilityofthecatalyst,easyremovalofthecatalystfromthereactionmixturebyfiltration,reusabilityofthecatalystforseveraltimeswithoftenminimallossofactivity,and,remarkably,abetterperfor-mancethanhomogeneousPdcatalystsinaconsiderablenumberofcases.Ontheotherhand,catalysisbyPdonsolidsupportscanrequirehigherreactiontemperaturesandhavelimitationsinstereoselectivereactions.Pdcatalystssupportedbyinorganicandorganicmaterialscanalsoofferthepossibilityofcircumventingligandssuchasphosphinesorarsinesincertaincasesandoftendonotneedwater-andoxygen-freeconditions.
ThemajorityofcatalystsappliedsofararePd/Ccatalysts,whicharecommerciallyavailableinmostcasesandcandirectlybeused.OthersupportedPdcatalystshavetobepreparedbytheuser.TheycanprovideadvantagesoverPd/C,andtheycanallowtuningofthepropertiesofthecatalyst.Manyactivitiescanbeexpectedinthisfieldinfuture.Themechanismofmostofthecouplingreactionscatalyzedbysolid-supportedPdisstillunclear.Futureresearchinthisfieldwillhelptheunderstandingofthesometimescontradic-toryresultsinthisfield.IthasbeenincreasinglyacceptedthatmostheterogeneousPdcatalystscatalyzeinahomoge-neouswaybyleachedPdspecies,whichcanre-depositwhenthereactioncomestoanend.However,generalconclusionsaredifficulttoattainbecauseinmostcasesthemechanismofacertainreactionisaffectedbytheconditionsverymuch.AlthoughtherearealsoothermoderntrendsinPdcatalysis,suchaspolymer-supportedPd,Pdnanoparticles,orPdclusters,itcanbeexpectedthattheapplicationofPdsupportedbyinorganicmaterialswillgainincreasingim-portanceandapplicationinfuture.
170ChemicalReviews,2007,Vol.107,No.111.AbbreviationsAc
acetyl
Aliquat336methyltrioctylammoniumchloride
(A336)aq
aqueous
[bmim]PF61-butyl-3-methylimidazoliumhexafluorophosphateBnbenzyl
BOC
tert-butoxycarbonylBu(n-Bu)n-butylt-Butert-butylcat.catalyst
concnconcentrationconvconversion
CTABcetyltrimethylammoniumbromideDIPEA
diisopropylethylamineDMA(DMAc)N,N-dimethylacetamideDME1,2-dimethoxyethaneDMFN,N-dimethylformamide
Dppb1,4-bis(diphenylphosphino)butaneDppp1,3-bis(diphenylphosphino)propaneequivequivalentEtethyl
FSMonekindofmodifiedsilicaGCgaschromatography
GLCgas-liquidchromatographyHAPhydroxyapatiteHexhexyl
HPLChigh-pressureliquidchromatographyIPAisopropylalcohol
LDHlayereddoublehydroxideMCM-41onekindofmesoporoussilicaMemethylminminuteMWmicrowaveMOMmethoxymethyl
NAILnonaqueousionicliquidNaphnaphthyl
NHCnitrogen-containingheterocycliccarbineNMAcN-methylacetamideNMP
N-methylpyrrolidone
[OMIM]BF41-octanyl-3-methylimdiazoliumtetrafluoroboratePenpentylPhphenylPrpropylPypyridine
RTroomtemperatureselect.selectivity
SBAkindofstructuredmesoporoussilicattime
T
temperature
TBABtetrabutylammoniumbromideTEAtriethylamine
TEGtetra(ethyleneglycol)THFtetrahydrofuraneTstosyl
USultrasound
Ytypeoffaujasitewithspecificstructural,physical,andchemicalproperties
ZSM-5
typeofsyntheticzeolitewithspecificstructuralproperties
12.AcknowledgmentsWegratefullyacknowledgeimportantsuggestionsmadebythereferees.WearethankfultoDr.MichaelPa¨tzelforproof-readingthemanuscript.
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