ASC_D400980e杜宝新ASC文章

1DOI:10.1002/adsc.20140098023Chemo-ControlledCross-CouplingofDi(hetero)arylDisulfides45withGrignardReagents:CÀCvs.CÀSBondFormation678Bao-XinDu,aZheng-JunQuan,a,*Yu-XiaDa,aZhangZhang,a

andXi-CunWanga,*

109

aLaboratoryofEco-Environment-RelatedPolymerMaterials,MinistryofEducation,China.GansuKeyLaboratoryof11PolymerMaterials,CollegeofChemistryandChemicalEngineering,NorthwestNormalUniversity,Lanzhou,Gansu12730070,People sRepublicofChina

13E-mail:quanzhengjun@http://wendang.chazidian.comorwangxicun@http://wendang.chazidian.com

1415Received:October13,2014;Revised:January26,2015;Publishedonline:&&&&,0000

1617SupportinginformationforthisarticleisavailableontheWWWunderhttp://wendang.chazidian.com/10.1002/adsc.201400980.181920avarietyofaromaticmoietiesandsulfur-containing21reagents.[4,5]Severalpapersdealingwiththereactions22ofalkenyl,vinyl,andarylsulfideswithGrignardre-23agents,mediatedbyNiorPdcatalysts,andleadingto24alkenesandbiarylcompounds,havebeenpublish-25ed.[5f,6]SincethepioneeringworkofLiebeskind,in26whichPd/Cu(I)carboxylatewasemployedasacata-27lysttoachievecopper-mediateddesulfurativecou-

plingoforganosulfurcompounds,thesecompounds28haveattractedconsiderableinterestasalternative29candidatesfororganohalidereagentsamongsynthetic30organicchemistsinthepastdecade.[7]Recently,some3132examplesofRh-orPd-catalyzedcross-couplingreac-33tionsofarylmethylsulfideswithorganoboronoror-

elegant

34ganozinccompoundswerereported.Inthese

methods,thecross-couplingreactionwasrationalized

35byaCÀScleavagepathwaytoconstructthenewCÀC36bond.[8,9]

37Itiswellknownthatdisulfides(R38Transitionmetal-catalyzedCÀCandCÀheteroatom2S2)areanimpor-

tantclassoforganosulfurreagentsfortheconstruc-

39cross-couplingreactions,asversatileandeffectivetionofCÀSbonds,andvariousnucleophilicreagents40methodsinorganicsynthesis,[1,2]playasignificantrolehavebeen

41inmaterialschemistryandmedicinalchemistry.Gen-Àemployedtoreactwithdisulfidestocon-

structCSbondsthroughSÀSbondcleavage

42erally,suchproceduresinvolvethecouplingofanac-(Scheme1,patha).[10–15]However,examplesofthe43tivatedelectrophilicsubstratewithanucleophilecouplingbetweendisulfidesandGrignardreagents44throughatransitionmetal-mediatedcross-couplingremainlimited.In1997,Riekereportedoneexample45reaction.Inthepastdecades,greateffortshavebeenofacross-couplingbetween3-thienylmagnesium46devotedtoextendingthisreactiontodifferentelec-iodideandalkyldisulfides,affording3-alkylthiothio-47trophiles.However,inmostcases,theelectrophilesphenesinmoderateyield.[11a]Then,Glassandco-48wereconfinedtoarylandalkenylhalidesduetotheirworkersusedmeta-terphenylGrignardreagentsto49higherreactivitytowardstransitionmetalcatalysis.[3]reactwithMeSSO

50Therefore,thedevelopmentofnewtypesofelectro-2MeorPhSSPh,synthesizingun-

symmetricaldiarylsulfides.[11b]Therearenoreports

51philesisstillinhighdemand.[3a]ontheutilizationofaniron-catalyzedreactionofdi-52Currently,organosulfurcompounds,presentinsulfideswithGrignardreagentstorealizethecon-53manybiologicallyactivecompounds,arewidelyusedstructionofaCÀCbond,althoughonepaperfrom54asbuildingblocksinorganicsynthesisandreceiveItamietal.describedtheCÀCcross-couplingreaction55

considerableattention.Somemethodsforthecon-ofalkenylsulfideswithGrignardreagentsusing

structionofCÀSbondshavebeendevelopedusingFe(acac)3asacatalyst.[16]Ourgrouprecentlydevel-Adv.Synth.Catal.0000,000,0–0 2015Wiley-VCHVerlagGmbH&Co.KGaA,

Weinheim1

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1homocoupling)(entry2).SimilartoFe(acac)3,ferro-2cenegaveboth3aaand4aa,andhighertemperatures3andlongertimesimprovedtheyieldoftheCÀCcou-4plingproduct(entries3–5).Itwasdiscoveredthatfer-5roceneatalowertemperature(À208C)producedthe6mostpromisingresults,providing3aain74%yieldin7ashortertime(entries6and7).Loweringthetemper-8ature(entry8)orraisingtheequivalentsof2a

(1a:2a=1:4.8)(entry9)didnotprovidebetterresults.

109UseofanexcessofGrignardreagentdecreasedthe11selectivity,resultinginaslightlyloweryieldoftheCÀ12Scouplingproduct(entry9comparedwithentry7).13Withrespecttoitsoutstandingperformanceand14lowerprice,ferrocenewaschosenasabettercatalyst15fortheCÀScouplingreaction(entry7),although16Pd(OAc)2wasalsoanefficientcatalystfavoring3aa17(entry10).

18WiththebestreactionconditionsforCÀSbondfor-19mationestablished,CÀCbondformationwasconsid-20Scheme1.StrategyfortheconstructionofCÀCandCÀSered.Frombondsthroughthecouplingofdisulfides.

21ÀtheresultsinTable1,highertemperatures

favoredCCbondformation,buttheyieldwaspoor

22(Table1,entry5).Toreversetheselectivity,withthe23opedthepalladium-andcopper-catalyzeddesulfura-purposeofhighlyselectiveformationoftheCÀCcou-24tivecross-couplingreactionsofamines,arylboronicplingproduct4aa,differentPdcatalystswerethen25acidsandalkynesÀwithdisulfidesaselectrophilestoscreened.TheuseofPdCl

26generateCCandCÀNbonds(Scheme1,pathb).[17]1:2.4gavetheCÀScoupled2withamolarratioof

1a:2a=3aaasthemajor

27Itwaslogicaltoquestionwhetherdisulfidescouldproduct(entry11).However,analterationofthe

alsoserveaselectrophilicpartnersinreactionswithmolarratioto1:4.8resultedintheformationof4aa28Grignardreagentstoachievetheselectiveformationin57%yieldwith79:21selectivity(entry12).When29ofCÀCandCÀSbonds.Pd(OAc)

30Herein,wereportourworkonthereactionofdi(-2,Pd(PPh3)4,orPdCl2(dppf)

selectivity2wasemployed

asthecatalyst(entries13–16),thewasre-

31hetero)aryldisulfideswithGrignardreagents,whichversed.Agoodyield(73%)andselectivity(97:3)32hasresultedintheconstructionofCÀSandCÀCwereobtainedat08Ctoroomtemperaturefor2h33bondsunderFe-andPd-catalyzedconditions,respec-(entry13).Theyieldof4aadecreasedathighertem-34tively.peratures,withtheformationofthehomocoupled35Interestingly,thereactioncatalyzedbyanFecata-productof2a(entry17).Then,solventscreeningwas36lystreadilygivestheCÀSbondformationproduct,performed,and1,4-dioxanewasbetterthanTHF37whereasthePdcatalystfavorsCÀCbondformation(entry18).Finally,atrialofthereactionintheab-38(Scheme1,pathc).Suchacatalyst-basedcontrolofsenceofacatalystandligandwasperformed,and3aa39thechemoselectivitywouldprovideahighlyselectivewasobtainedastheonlyproductin35%yield40entryintodifferentproductsfromthesamesub-(entry19).

41strates.Controlofselectivity–thesamesubstratesThen,thegeneralityofthisCÀScross-couplingwas42areappliedfordifferentproducts–remainsoneofinvestigatedundertheoptimizedFe-catalyzedcondi-43themostimportantchallengesinorganicchemistry.[18]tions(Table1,entry7).Ingeneral,avarietyofdi(he-44Amongthemethodsthathavebeenemployed,con-tero)aryldisulfidessmoothlyreactedwithdifferent45trolofselectivitybycatalystshasbeenproventobeGrignardreagents(RMgBr),leadingtotheCÀS46verybeneficial.[19]cross-couplingproducts(Scheme2).Bothelectron-47Initially,ourstudieswerefocusedontheselectivityrichmagnesiumbromides,suchasmethyland2-me-48ofCÀCandCÀScouplings.Thereactionof1awiththoxyphenyl,andelectron-poormagnesiumbromides,49anexcessamountofPhMgBr(2a)wasusedassuchas4-chlorophenyl,underwentCÀScross-cou-50amodelreactiontotestthepossibilityofselectiveCÀplingstodelivertheproducts3ab–3ahingoodyields.51CandCÀScoupling.First,Fecatalystswereapplied,Thienyland1-naphthylgroupscouldalsobetolerated52andtheuseofFe(acac)inthisreaction.Similarly,aseriesofdiheteroaryldi-53couplingproducts4aa3resultedinbothCÀCandCÀ

Sand3aain8%and48%sulfides(1)withvariousGrignardreagents(2),in-54yield,respectively(entry1),whileFeClcludingethyl-,butyl-,hexyl-,heptyl-,andnonylmag-55

productin42%yieldwithformation3gave3aaas

thesoleofthenesiumbromides,selectivelygeneratedCÀScoupledhomocouplingproductoftheGrignardreagent(GRproducts3ai–3amin71–79%yield.Theuse

of2asc.wiley-vch.de 2015Wiley-VCHVerlagGmbH&Co.KGaA,WeinheimAdv.Synth.Catal.0000,000,0–0ÝÝThesearenotthefinalpagenumbers!12345678109111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455

1Table1.Optimizationofthereactionconditions.

[a]

2345678

EntryCatalyst/Ligand1a:2a[c]Temp.[8C]TimeYield[%][b]Selectivity1093aa4aa3aa:4aa11121Fe(acac)/–1:4.80–r.t.4h4886:14132FeCl3

3/–1:4.80–r.t.4h42<295:5

143ferrocene/–1:4.80–r.t.4h551282:18

4ferrocene/–1:4.80–r.t.24h511676:24155ferrocene/–1:4.80–6524h482467:33166fe(acac)3/–1:2.4À202h63<593:7177ferrocene/–1:2.4À200.5h74<297:3188ferrocene/–1:2.4À400.5h65<297:3199ferrocene/–1:4.8À200.5h701088:122010Pd(OAc)2/DPE-Phos1:2.40–r.t.0.5h71889:112111PdCl1:2.40–r.t.4h66790:102212PdCl2/PPh31:4.80–r.t.4h155721:79

13Pd(OAc)2/PPh

/DPE-Phos31:4.80–r.t.4h<2733:97

2314Pd(OAc)2

2/DPE-Phos1:4.80–r.t.2h<2733:97

2415Pd(PPh3)1:4.80–r.t.2h5627:932516PdCl41:4.80–r.t.2h<5657:932617Pd(OAc)2(dppf)21:4.8654h<2415:952718dPd(OAc)2/DPE-Phos

1:4.80–r.t.2h<2782:98

2819–2/DPE-Phos

1:2.4r.t.2h35––

29[a]Conditions:0.2mmol1a,2a(1.0MinTHF),catalyst(5mol%),in3mLTHF,underN

30noted.2atmosphere,unlessotherwise31[b]Isolatedyieldbasedondisulfide1a(2mmol).

32[c]Molarratioof1ato2a.[d]

33Thereactionwascarriedoutin2mLTHFand1mL1,4-dioxane.

3435branchedisopropylmagnesiumbromideandthemoretheCÀScoupledproducts3ghand3hawereobtained36reactivebenzylmagnesiumbromidedidnotdecreaseasuniqueproducts,showingaloweractivityinthis37theefficiencyofthereaction,givingthedesired3an–process.Thisreactivityofdisulfideswasalsoobserved383aoingoodyields.Notably,1,2-di(pyridin-2-yl)disul-inapreviousstudy.[17b]

39fideandaryldisulfidesalsoresultedin71–77%yieldsAfterthetestswithsymmetricaldiheteroaryldisul-40of3fa–3ha.fides,anunsymmetricaldisulfide(1i)substratewas41Next,theoptimizedPd-catalyzedconditionswereexamined.Whenthereactionof1iwith2awasper-42exploredtotestthegeneralityoftheCÀCcouplingformedundertheCÀCcouplingconditions,amixture43(Scheme3).Differentdiheteroaryldisulfides(1)of4aa(70%),4fa(8%),andtheCÀScouplingprod-44couldbewelltoleratedinthisprocess,leadingtotheuct3fa(48%)wasobtained(Scheme4).45desiredproducts4.DifferentGrignardreagentswithInadditiontothedisulfideemployed,theCÀScou-46botharomaticandaliphaticgroupsgavetheexpectedpledproduct3aacanfurtherreactwith2aunderthe47products4aa–4caingoodyields,whereasthe1,2-di(-standardCÀCcouplingconditions.TheCÀCcoupling48pyridin-2-yl)disulfidereactedwithphenyl-andhexyl-product4aawasisolatedin71%yieldtogetherwith49magnesiumbromidesmoothlyat658Cfor6h,yield-thehomocoupling

50ingthedesiredproducts4faand4fkinloweryields.Àproduct2a(Scheme5).Thisresult

impliedthattheCScoupledproduct3mightbean

51Comparedwiththetestednitrogen-containingdihe-importantintermediatefortheCÀCcouplingproduct.52teroaryldisulfides,aryldisulfidesshowedmuchlowerThecontrolexperimentsusediodobenzeneinstead53reactivity.Forexample,thereactionof1,2-diphenyloftheGrignardreagenttocomparethereactivityof54disulfideand1,2-bis(4-nitrophenyl)disulfidewithar-aGrignardreagentwithahalogensubstituent55

ylmagnesiumbromidesdidnotresultinanyCÀCcou-(Scheme6).Thereactionofdisulfide

pledproductundersimilarreactionconditions,butÀ1awithiodo-

benzenewasperformedundertheCS(Patha)and

Adv.Synth.Catal.0000,000,0–0 2015Wiley-VCHVerlagGmbH&Co.KGaA,Weinheimasc.wiley-vch.de3

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1112131415161718192021222324252627282930Scheme2.Scopeoftheferrocene-catalyzedCÀScross-couplingofdi(hetero)aryldisulfidesandGrignard

reagents.31323334353637383940414243444546474849505152535455

Scheme3.ScopeofthePd-catalyzedCÀCcross-couplingreactionbetweendiheteroaryldisulfides1a–1fandGrignardre-

agents2.

4asc.wiley-vch.de 2015Wiley-VCHVerlagGmbH&Co.KGaA,WeinheimAdv.Synth.Catal.0000,000,0–0ÝÝThesearenotthefinalpagenumbers!12345678109111213141516171819202122232425262728293031323334353637383940414243444546474849505152535455

1acterizedandithasbeenproventhattheyarethe2mostactivecatalystsforthecross-coupling.However,3itremainslargelyunknownifandhowlow-valentor-4ganoironspeciesreactwithGrignardreagentsinsolu-5tion.[20]Alternatively,amechanismbasedonaddition/6eliminationwasalsoproposed.[16]Recently,Netopro-7posedthatthecation[Fe(C+5H5)](m/z=121),formed8asaconsequenceofferrocenedecomposition,might

beastrongerLewisacidandcapableofcatalyzingthe

109Biginellireaction.[21]However,thecation[Fe(C5H5)]+11Scheme4.Selectivecross-couplingofunsymmetricaldisul-(m/z=121)wasnotdetectedbyESI-MSinthereac-12fide1i

.tionof1awith2aatroomtemperature.Wesurmised13thatasimilaraddition/eliminationmechanismmight14bepossibleintheferrocene-catalyzedCÀScoupling15reaction.Finally,wehavetostressthattheexact16mechanismisyettobeestablishedwithmoreexperi-17mentalandtheoreticalstudies.

18Inconclusion,wehavedevelopedsimpleandeffi-19cientferrocene-andPd(OAc)2-catalyzedcross-cou-20plingsofdi(hetero)aryl

21ÀdisulfideswithGrignardre-

agents,providingCSandCÀCbondswithexcellent

22chemoselectivityundermildconditions.Unlikethe23previousreports,Grignardregentswereusedasnu-Scheme5.Identifyingthecomponentsofthecross-coupling

24reaction.cleophiles,ÀgivingahighselectivitybetweenCÀCand25CSbondformationandproducingalibraryofmole-26culeswithpyrimidineandpyridinescaffoldsingood27isolatedyields.Theselectivitywithdifferentmetal

catalystsmaybeworthyofinvestigation.Further28studies,includingsyntheticapplicationsofthisreac-29tionandtheeffectsofthecatalystontheselectivity,

30arebeingcarriedoutinthisgroup.

313233ExperimentalSection

3435GeneralProcedurefortheSynthesisofThioethers336(3aa–3gh)

3738Underanitrogenatmosphere,1(0.2mmol,109mg)andfer-39rocene(5mol%,1.9mg)wereaddedtoaSchlenktube.The

tubewasstopperedanddegassedwithnitrogenthreetimes.40Scheme6.Reactivityofiodobenzeneinthecross-couplingDistilledTHF(3mL)wasaddedbysyringeandthemixture

41withdisulfide1a.wasstirredfor15min.Then,theGrignardreagent242(0.48mmol,2.4equiv.,1.0MsolutioninTHF)wasadded43undernitrogenusingasyringe.Thereactionmixturewasal-44CÀC(Pathb)couplingconditions.Unfortunately,nolowedtostirforapproximately0.5hatÀ208Candthereac-45desiredproduct3aawasobtained,andthestartingtionwasmonitoredbyTLCanalysis.Then,2mLwaterwere46materialswererecovered.Whenthereactionthatwasaddedtothemixturetoquenchthereaction,theorganic47catalyzedbyPd(OAc)componentswereextractedwithethylacetateandthere-

2inthepresenceofDPE-Phos

48washeatedat1008Cfor10h,onlya20%yieldofCÀsultingextractwasevaporatedundervacuumandfurther49Scoupledproduct3aawasobtainedwithoutformingpurifiedbycolumnchromatographyonsilicagelwithpetro-50theCÀCcoupledproduct4aa(Pathc).Theseresultsleumether/ethanol(30:1)togivethecorrespondingprod-51revealeducts3.

52Àthatdisulfidesarefavoredoverarylhalides

intheCC/CÀScross-couplingreactions.

53Generally,themechanismofiron(IIIorII)-cata-GeneralProcedurefortheDesulfurativeCoupling54lyzedcross-couplingofarylhalideswithGrignardre-Process(4aa–4fk)

55

agentshasbeenstudiedthoroughly.Low-valentironUnderanitrogenatmosphere,1(0.2mmol,109mg),species(low-valentironcomplexes)havebeenchar-Pd(OAc)2(10mmol,2.4mg),andDPE-Phos(12m

mol,

Adv.Synth.Catal.0000,000,0–0 2015Wiley-VCHVerlagGmbH&Co.KGaA,Weinheimasc.wiley-vch.de5

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