umpolung of hemiaminals： titanocene-catalyzed dehydroxylative radical coupling reactions with activated alkenes

1、RadicalReactionsDOI:10.1002anie.201210088UmpolungofHemiaminals:TitanoceneCatalyzedDehydroxylativeRadicalCouplingReactionswithActivatedAlkenesXiaoZhengXiJieDaiHongQiuYuanChenXiYeJieMaPeiQiangHuangBis(cyclopentadienyl)tita

2、nium(III)chlide(Nugent?sreagent)[1]isanefficientsingleelectronreductanthasbeenusedasaversatiletoolinganicsynthesis[23]owingtotheeaseofhlingitsfunctionalgroupcompatibilityabroadarrayofreactionsthatcanbeeffectedunderrelati

3、velymildconditions.Today[Cp2TiCl]isusedasacatalystfseveraltypesofradicalreactionsbyemployingacatalyticamountof[Cp2TiCl2]asacatalystprecursametal(suchasMnZnAlInMgSm)[4]asacoreductantinthepresenceofTMSClproticacids.Amongth

4、e[Cp2TiCl]catalyzedradicalreactionsreductiveepoxideopeningreaction[5]firstdemonstratedbyNugentRajanBabu[1]thenbyGans?ueretal.[5bc]hasbeenthesubjectofintensivestudiesfoundapplicationsinnaturalproductsynthesis.[6]Inthisrea

5、ctiona[Cp2TiCl]initializedhomolysisofC?Obondsisinvolved.AsanextensionofthisfeatureBarrerocowkersrecentlydescribedadeoxygenationofalcoholsusuallymediatedbyastoichiometricamountof[Cp2TiCl].Inadditioncatalyticexampleshaveal

6、sobeenrepted.[7]Inviewoftheseprecedentsthe[Cp2TiCl]catalyzeddehydroxylativecouplingreactionsofalcoholsotherhydroxycontainingcompoundssuchassugarshemiacetalshemiaminalsseemedpossible.Itisknownthatumpolungofhemiaminalscanp

7、rovideradicalcarbonintermediatesinapositiontoaminogroupsthroughdehydroxylationoneelectronreductionofthecrespondingcarbeniumions.[8]WehaverecentlydevelopedaSmI2mediateddehydroxylativeradicalcrosscouplingreactionofhemiamin

8、alswithactivatedalkenes[Scheme1Eq.(1)][9]whichwasassumedtoproceedthroughaSmI2basedsingleelectronreductionofNacyliminiumions.ThismethodologyprovidesausefulefficientstrategyfC?Cbondfmationatthecarbonatomsinapositiontoamino

9、groupscanbeemployedfthesynthesisofalkaloidsotherpharmaceuticals.[10]Basedontheseconsiderationsitwouldbeparticularlyinterestingvaluabletodeveloptransitionmetalcatalyzeddehydroxylativeradicalcouplingreactionsofhemiaminalsu

10、ndermildconditionswhichhavenotbeenreptedsofar.Weenvisionedthatthesingularabilityof[Cp2TiCl]tocleaveaC?Obondmighthelpustoachievethisgoal.Hereinwerepttitanocenecatalyzeddehydroxylativeradicalcouplingreactionsofhemiaminalsw

11、ithactivatedalkenes[Scheme1Eq.(2)].Thisnovelreactionwasperfmedbyusinga[Cp2TiCl2](cat.)MgTMSClreductionsystem[11]inthepresenceoftertbutanol.Anapplicationofthisradicalmethodologyhasbeendemonstratedbyanefficientsynthesisof(

12、?)910diepistemoae.Webeganourstudywiththetreatmentofhemiaminal1[12]methylacrylate(2.0equiv)with[Cp2TiCl2](0.025equiv)Mgpowder(2.0equiv)TMSCl(2.0equiv)thedesiredcrosscouplingproduct2awasobtainedin54%yield(Table1entry1).The

13、influenceofotherreactionfactsincludingLewisacidsproticadditivesmetalswassystematicallyinvestigated.TMSClplayedapivotalroleinthisreaction.TheuseoftBuOHgavethefastestreactionshighestyields(Table1entry3versusentry2).Afterex

14、tensivetrialstheoptimizedcouplingconditionsweredefinedascarryingoutthereactionsinTHFwith[Cp2TiCl2]asacatalystprecurs(0.025equiv)magnesiumturningsasacoreductant(5.0equiv)inthepresenceofTMSCl(4.0equiv)tBuOH(4.0equiv).Using

15、thiscatalyticsystemtheScheme1.Dehydroxylativeradicalcouplingreactionsofhemiaminalswithactivatedalkenes.Cp=cyclopentadienylEWG=electronwithdrawinggroupTMS=trimethylsilyl.[]Assoc.Prof.Dr.X.ZhengX.J.DaiH.Q.YuanC.X.YeJ.MaPro

16、f.P.Q.HuangDepartmentofChemistryFujianProvincialKeyLabatyofChemicalBiologyCollegeofChemistryChemicalEngineeringXiamenUniversityXiamenFujian361005(P.R.China)Email:c.Prof.Dr.X.ZhengKeyLabatyofSyntheticChemistryofNaturalSub

17、stancesShanghaiInstituteofganicChemistryChineseAcademyofSciences(P.R.China)[]WearegratefultotheNationalBasicResearchProgram(973Program)ofChina(GrantNo.2010CB833200)theNSFofChina(21172183)theProgramfChangjiangScholarsInno

18、vativeResearchTeaminUniversity(PCSIRT)theNaturalScienceFoundationofFujianProvinceofChina(No.2010J01050)theFundamentalResearchFundsftheCentralUniversities(No.CXB2011015)NFFTBS(No.J1210014)ffinancialsuppt.WealsothankProf.L

19、inFengXieDr.AiEWangofXMUfkindhelpfuldiscussionsonthispaper.SupptinginfmationfthisarticleisavailableontheWWWunder:dx.doi.g10.1002anie.201210088..AngewteCommunications3494?2013WileyVCHVerlagGmbH&Co.KGaAWeinheimAngew.Chem.I

20、nt.Ed.2013523494–3498theadditionofGrignardreagentstosucciniestheirsuccessfulcouplingwithactivatedalkeneswouldallowthefmationofquaternarycarboncentersinapositiontoaminogroups.[13]Thedesiredaaminodisubstitutedglactamswerep

21、roducedinmoderatetogoodyields(Table4).ThecouplingseemedtobeaffectedbythesterichindranceofRgroupsinthehemiaminalselectronwithdrawinggroupsintheactivatedalkenes.ReactionsofhemiaminalswithbulkierRgroupsprovidedproductsinlow

22、eryieldswhencoupledwiththesameactivatedalkene.Furthermeincouplingreactionsofthesamehemiaminalwithdifferentacrylatesthemebulkytertbutylacrylategavetheproductinaloweryieldthanmethylacrylate(Table4entry2versusentry1entry5ve

23、rsusentry4entry8versusentry7).Meovercouplingreactionsofthreehemiaminalswiththeleasthinderedacrylonitrileconsistentlygavethehighestyields(Table4entries369).Tofurtherdemonstratetheadvantageofthistitanocenecatalyzedreaction

24、overthepreviouslyreptedSmI2mediatedreactionwithregardtobothefficiencyapplicability[910]alargescalesynthesisof2awasperfmed.Followingtheestablishedgeneralprocedureftitanocenecatalyzedcrosscouplingreactiononlya100mLroundbot

25、tomflaskwasneededfthereactionproduct2awaseventuallyobtainedin83%yieldfromhemiaminal1(2.16g11.3mmol).Comparativelyatleast450mLofasolutionofSmI2inTHFwasrequiredfthepreparationof2aonthesamescaleusingthepreviouslyreptedSmI2m

26、ediatedreaction.[10a]Wealsoexpledtheplausiblemechanismoftitanocenecatalyzeddirectdehydroxylativecrosscouplingreactionofhemiaminalswithactivatedalkenes.NMRexperimentswithhemiaminal1indeuteratedtetrahydrofuranshowedthatins

27、ituchlinationofthehemiaminaloccurredupontreatmentwithTMSCl(comparewiththeSupptingInfmation).BasedontheseobservationsthefirststepoftitanocenecatalyzeddirectdehydroxylativereactionspresumablyinvolvestheTMSClpromotedconvers

28、ionofthehemiaminaltothechlolactamAassuggestedbyPetersonJacobsen[14](Scheme2).SubsequentlychlolactamAisreducedby[Cp2TiCl]togenerateaacylaminoalkylradicalB[8a910]whichisthentrappedbyanactivatedalkenetogiveradicalC.Furtherr

29、eductionofradicalCbyanother[Cp2TiCl]complexgeneratesthetetravalenttitaniumsaltDwhichiseventuallyprotonatedtogivethecrespondingcrosscouplingproduct.ThebeneficialeffectoftBuOHmayberibedtoitssynergisticeffectwithTMSClaccele

30、ratingthechlinationofhemiaminalsaswellastheprotonationoftitaniumsaltsDbyinsitugenerationofHCl.Todemonstratethesyntheticvalueofthistitanocenecatalyzedreactionwedevelopedanefficientsixsteptotalsynthesisof(?)910diepistemoae

31、.[1516]StemoaeoneoftheStemonaalkaloidswasisolatedfromtheChinesetraditionalmedicineStemonatuberosaLourbyXucowkersin1992.[17]RecentlythegroupsofKhimCossyhaveindependentlydevelopedanasymmetricsynthesisof(?)910diepistemoae[1

32、5c]astereoivesynthesisofitsracemat[15ab]respectivelybyemployinga7exotrigradicalringclosurestrategy.Westartedoursynthesisfromcommerciallyavailable3methyl2(5H)furanone14whichwastreatedwithTMSOTfinthepresenceofEt3Ntogivesil

33、yloxyfuran15in78%yield.AMukaiyama–Michaelreaction[18]ofsilyloxyfuran15withacroleinunderthecatalysisofpyrrolidine–AcOHat?408Cgavealdehyde16in64%yieldwhichwasreducedbyBH3inTHFat?308Ctogivealcohol17in93%yield.Condensationof

34、alcohol17withsucciniemediatedbyPh3PDIADaffdedNsubstitutedsuccinie18in91%yield.Treatmentofie18withNaBH4inmethanolat?108Cproducedhemiaminal19in92%yield.Basedontheaboveestablishedmethodtheintramolecularradicalcrosscouplingr

35、eactionofhemiaminal19underwentsmoothlyutilizingthecatalyticsystem[Cp2TiCl2]MgTMSCltogive(?)910diepistemoae(20)in32%yieldasthesolediastereomeralongwithTable4:Titanocenecatalyzedfmationofquaternarycarboncentersinapositiont

36、oaminogroupsfromhemiaminals81012.EntryHemiaminalRActivatedAlkeneProduct(Yield[a][%])18Me9a(82)28Me9b(77)38Me9c(84)410Et11a(81)510Et11b(72)610Et11c(83)712Bn13a(75)812Bn13b(68)912Bn13c(81)[a]Yieldsofisolatedproducts.Scheme