搜索
KulinkovichReaction库林科维奇反应KulinkovichCyclopropanationTheKulinkovichReactionallowsthepreparationofcyclopropanolderivativesbythereactionofGrignardreagents(ethylorhigher)withestersinthepresenceoftitanium(IV)isopropoxideascatalyst.Kulinkovich反应（Kulinkovichreaction），又称Kulinkovich环丙烷化反应、Kulinkovich环丙化反应（Kulinkovichcyclopropanation），由O.Kulinkovich等人在1989年报道。在异丙醇钛(Ⅳ)（Ti(OiPr)4）催化下，乙基或更高级的格氏试剂（有β-氢）与酯反应生成环丙醇衍生物。一般认为，反应机理中，首先为两分子格氏试剂与烷氧基钛进行转金属作用，产生一个对热不稳定的二烷基二烷氧基钛络合物，后者很快发生β-氢消除、歧化，放出烷烃并产生一分子取代钛杂环丙烷中间体(1)。该中间体作为1,2-双碳负离子等价物，其较弱的C–Ti键接受酯羰基的插入反应，得到恶钛杂环戊烷中间体(2)，并接下来重排为酮(3)。上述插入过程重复一次，(3)的羰基分子内插入C–Ti键中，再进行一次烷基化，得到环丙醇衍生物中间体(4)。这一步是总反应的限速步骤，被还原的钛(Ⅱ)亦在此步骤中被重新氧化为钛(Ⅳ)。此步的产物(4)是一种烷氧基钛化合物，与反应使用的烷氧基钛催化剂类似，(4)也可以与格氏试剂发生转金属作用，再生烷基钛，从而完成此反应的催化循环。而且，此一步的另一产物环丙醇镁盐(5)，经过水解，即得游离的环丙醇。若使用比乙基更为高级的格氏试剂，产物中将会产生两个新的立体中心，并且，反应底物中不含螯合基团时，反应也有很高的非对映选择性，这是此反应的一个特点。有认为此非对映选择性是由于恶钛杂环戊烷(3)向环丙醇钛盐(4)转化一步过渡态中，底物的C–H键与钛原子之间形成的抓氢键作用而造成的。MechanismoftheKulinkovichReactionIfethylmagnesiumbromideisused,theformationofethaneandatraceofethenecanbeobserved.TwoequivalentsoftheGrignardreagentreactwithtitanium(IV)isopropoxidetogiveathermallyunstablediethyltitaniumcompound,whichrapidlyundergoes经受β-hydride氢化物eliminationwiththelossofethanetoyieldthesubstitutedtitanacyclopropane:取代钛杂环丙烷中间体Thetitanacyclopropanereactswiththeesterasa1,2-dicarbanion双碳负离子equivalenttoproduceacyclopropanolaftera2-foldalkylation2倍烷基化:Titanium(II)isreoxidizedtotitanium(IV)overthecourseofthisadditionprocess.ThelastintermediateinthesequencecanberecognizedasaTi(OR'')4species,whichcanundergoreactionwithEtMgBrsimilartoTi(OiPr)4.Thus,titanium(IV)isopropoxidecanbeusedincatalyticamounts:Theproductionofethenehasbeenattributedtoasidereactionofthetitanacyclopropanewithadditionaltitanium(IV)isopropoxidetoafford2equivalentsoftitanium(III)isopropoxide(Kulinkovich,Synlett2004,77.DOI).Thisnon-productivesidereactionreachesamaximumastheratiooftitanium(IV)isopropoxidetoEtMgBrapproachesastoichiometry[,stɒɪkɪ'ɒmɪtrɪ]of1:1.However,thissequencecanbeusefulforthegenerationoflowvalenttitaniumcompoundsthatcanbeutilizedforexampleinPinacol频哪醇CouplingReactions.Thereactionofhigheralkylmagnesiumhalides(e.g.PrMgX)leadstoproductswithtwostereocenters,andhighdiastereoselectivitycanbehadintheabsenceofanychelating螯合substituentsinthesubstrate:Forthisreason,thereactionisalsoapplicabletothesynthesisofhighersubstitutedcyclopropanols.Thedisproportionaspectofthemechanismmeansthatonlyoneofthetwoorganomagnesiumligandsisincorporatedintothereactionproduct,whichisaconcernwhentheGrignardreagentusedisnotacommercialitem.Twointerestingmodificationshelptoimprovetheatomeconomyformorespecializedligands.Onemethodistouseaterminalalkenethatcanundergoaligandexchange.Theexchangeisfastforstyrenes苯乙烯,andallowstheuseofEtMgBrastheGrignardreagent.Forotherterminalalkenes,thebulkiercyclohexylmagnesiumhalidescanbebeusedtoretardtheparticipationoftheinitiallyformedtitanium(II)speciesinthealkylationreactionandtopromotethereactionofthedesiredligandwiththeester.Sub-stoichiometricamountsoftitanium(IV)isopropoxidecanstillbeusedinthisligandexchangemodification.Intheothermodifiedprocedure,describedbydeMeijere,MeTi(OiPr)3isformedfirst,andastoichiometricamountisusedwithonly1.1eq.ofaGrignardReagent.Here,thedisproportionationproducesmethaneasagaseoussideproductandallowstheGrignardreagenttobefullyutilized:Formoreonthetopicof1,n-dicarbanionictitaniumintermediatesfrommonocarbanionicorganometallicsandtheirapplicationinorganicsynthesis,seearecentreviewbyKulinkovichanddeMeijere(Chem.Rev.2000,100,2789.DOI)SomeyearsafterthedevelopmentoftheKulinkovichReaction,ahighlyversatilepreparationofcyclopropylaminesfromamideswasworkedoutbydeMeijereandaconversionofnitrilesintoprimarycyclopropylamineswasdevelopedbySzymoniak.RecentLiteratureTitanium(IV)Isopropoxide-CatalyzedFormationof1-SubstitutedCyclopropanolsintheReactionofEthylmagnesiumBromidewithMethylAlkanecarboxylatesO.G.Kulinkovich,S.V.Sviridov,D.A.Vasilevski,Synthesis,1991,234.TheKulinkovichReactiononLactones.AConvenientApproachtoFunctionalizedCyclopropanolsA.Esposito,M.Taddei,J.Org.Chem.,2000,65,9245-9248.