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:SelectiveSynthesisof2-substituted-3-Halo-1H-indolesTangShia，b,XieYexianga,LiJinhenga*,WangNaixingb*aKeyLaboratoryofChemicalBiology&TraditionalChineseMedicineResearch(MinistryofEducation),CollegeofChemistryandChemicalEngineering,HunanNormalUniversity,Changsha,China(410081)bTechnicalInstituteofPhysicsandChemistry,ChineseAcademyofSciences,Beijing,China(100101)E-mail：jhli@hunnu.edu.cnAbstractAnovelandeffectiveprotocolforthesynthesisof2-substituted-3-halo-1H-indolesbyPdX2/CuX2-catalyzedannulationsof2-ethynylbenzenamineshasbeendeveloped.InthepresenceofPdX2andCuX2,theannulationreactionsofavarietyof2-ethynylbenzenamineswereconductedinmoderatetogoodyields.ItisnoteworthythatonlyN-acetylprotected2-ethynylbenzenaminescanundergothereactionsuccessfully.Keywords:Palladium(II)halide,copper(II)halide,annulation,2-ethynylbenzenamine,2-substituted-3-halo-1H-indoles.1.IntroductionIndoles,inparticular3-halo-substitutedones,haveattractedconsiderableeffortsontheirsynthesisbecausethisstructuralmotifiscommontoavarietyofbiologicallyactivealkaloidsandimportantpharmaceuticalsandvaluableintermediatesfororganicsynthesis.1-7Themostcommonlysyntheticapproachfor3-haloindolesisdirecthalogenatedindoleswithN-halosuccinimides,3halogen,4POX3/imidazole5andothers.6However,thereactionconditionsofthesemethodsaregenerallyinvolvehighlyacidicorbasicmedia.Otherdrawbacksofthesemethodsincludepoorselectivity,overhalogenation,sensitivitytoair/water,andnarrowfunctionaltolerance.Recently,theelectrophiliccyclizationsof2-ethynylbenzenaminesprovedespeciallyefficientforthesynthesisof3-haloindoles.7However,only3-iodoindoleswerepreparedfromthereactionofthecorresponding2-ethynylbenzenamineswithI2orIPy2BF4.Therefore,thedevelopmentofanewandgeneralapproachforforming3-haloindolesisstillsignificant.Veryrecently,wehavereportedanovelandselectivepalladium-catalyzedannulationsof2-alkynylphenolsmethodforthesynthesisof2-substituted3-halobenzo[b]furans.8InthepresenceofPdX2andCuX2(X=Br,Cl),2-substituted3-halobenzo[b]furanswereselectivelyobtainedasthemajorproductsusingHEt3NXasthepromoter.Herein,wewishtoreportthatthePdX2/CuX2systemwasextendedintheannulationsof2-ethynylbenzenaminessuccessfullytosynthesize2-substituted3-haloindolesinmoderatetogoodyields.Thisprocessrepresentsanovelapproachforthesynthesisof2-substituted3-haloindoles(Scheme1).NHAcR'PdX2/CuX2NAcXR'DCERRX=Cl,BrR=H,F,Cl,NO2R'=n-C8H17,Ph,t-butyl,CH2CH2OAcScheme1:PdX2/CuX2system-catalyzedannulationsof2-ethynylbenzenamines2.Resultsanddiscussion[b]furanswerepreparedselectivelyfromtheannulationsof2-alkynylphenolsusingPdX2andCuX2asthecatalyticsystem.Thus,weexpectedtoapplythePdX2/CuX2/HEt3NXsystemintheannulationsof2-ethynylbenzenamines(Table1).Asexpected,thePdX2/CuX2/HEt3NXsystemwaseffectivefortheannulationofN-(2-(dec-1-ynyl)phenyl)acetamide(1a)usingDCE(1,2-dichloroethane)asthesolvent.InthepresenceofPdBr2(5mol%),CuBr2(3equiv)andHEt3NI(0.2),91%GCyieldof1-(3-bromo-2-octyl-1H-indol-1-yl)ethanone(3a)wasobtainedalongwith8%GCyieldofaby-product2a,1-(2-octyl-1H-indol-1-yl)ethanone,fromthereactionofsubstrate1a(entry1).However,theyieldofthetargetproduct3awasdecreasedtosomeextentwhenHEt3NBr,NaOH,orHOAcwasusedtoinsteadHEt3NI(entries2-4).ItwasinterestinglytorevealthatN-(2-(dec-1-ynyl)phenyl)acetamide(1a)couldundergotheannulationreactionsmoothlywithoutHEt3NI(entry5).Subsequently,othersolventsincludingCH3CN,CH2Cl2andTHFwereexamined,andtheywerelesseffectivefortheannulationreactionthanDCE(entries5-8).Screeningresultsshowedthat3equivofCuBr2providedthebestresults(entries5and9-11).WithoutCuBr2,1-(2-octyl-1H-indol-1-yl)ethanone(2a)wasisolatedasthemajorproducttogetherwith5%GCyieldofthetargetproduct3a(entry9),whereastheyieldofthetargetproduct3awasenhancedsharplywhenCuBr2wasadded(32%yield/2equivofCuBr2,96%yield/3equivofCuBr2and90%yield/5equivofCuBr2;entries5,10and11).9TheotherblankexperimentsindicatedthatbothPdBr2andCuBr2playedacurialroleinthereactions.WithoutaPdsource,messyresultwasobservedinthepresenceofCuBr2alone(entry12),butintheabsenceofCuBr21-(2-octyl-1H-indol-1-yl)ethanone(2a)wasobtainedasthemajorproductusing5mol%ofPdBr2(entry9).Notethatgoodisolatedyieldof3aisstillachievedatroomtemperatureafterprolongingthereactiontimeinthepresenceofPdBr2(5mol%)andCuBr2(3equiv)(entry13).Finally,N-protectedgroupswerealsotestedunderthePdBr2/CuBr2catalyticsystem.Unfortunately,2-(dec-1-ynyl)benzenamine(1b),N-(2-(dec-1-ynyl)phenyl)benzamide(1c)andN-benzyl-2-(dec-1-ynyl)benzenamine(1d)werenotsuitablesubstratesfortheannulationreaction(entries14-16).Table1.Palladium-CatalyzedAnnulationReactionsof2-(Dec-1-ynyl)benzenaminesaNHRnC8H17PdBr2/CuBr2NRXnC8H17solvent+NRHnC8H17123GCyield(%)bEntryRAdditive(equiv)Time(h)231Ac(1a)Het3NI(0.2)DCE8(6)91(88)2Ac(1a)Het3NBr(0.2)DCE35173Ac(1a)NaOH(2.0)DCE64214Ac(1a)HOAc(2.0)DCE21645Ac(1a)⎯DCE096(92)6Ac(1a)⎯CH3CN21127Ac(1a)⎯CH2Cl234238cA