Kulinkovich Reaction库林科维奇反应.doc

Kulinkovich Reaction库林科维奇反应Kulinkovich Cyclopropanation The Kulinkovich Reaction allows the preparation of cyclopropanol derivatives by the reaction of Grignard reagents (ethyl or higher) with esters in the presence of titanium(IV) isopropoxide as catalyst.Kulinkovich反应（Kulinkovich reaction），又称Kulinkovich环丙烷化反应、Kulinkovich环丙化反应（Kulinkovich cyclopropanation），由 O. Kulinkovich 等人在1989年报道。在异丙醇钛()（Ti(OiPr)4）催化下，乙基或更高级的格氏试剂（有-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-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 CTi 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 CTi 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()亦在此步骤中被重新氧化为钛()。 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 CH 键与钛原子之间形成的抓氢键作用而造成的。Mechanism of the Kulinkovich ReactionIf ethylmagnesium bromide is used, the formation of ethane and a trace of ethene can be observed. Two equivalents of the Grignard reagent react with titanium(IV) isopropoxide to give a thermally unstable diethyltitanium compound, which rapidly undergoes经受 -hydride氢化物 elimination with the loss of ethane to yield the substituted titanacyclopropane: 取代钛杂环丙烷中间体The titanacyclopropane reacts with the ester as a 1,2-dicarbanion 双碳负离子equivalent to produce a cyclopropanol after a 2-fold alkylation2倍 烷基化:Titanium(II) is reoxidized to titanium(IV) over the course of this addition process. The last intermediate in the sequence can be recognized as a Ti(OR)4 species, which can undergo reaction with EtMgBr similar to Ti(OiPr)4. Thus, titanium(IV) isopropoxide can be used in catalytic amounts:The production of ethene has been attributed to a side reaction of the titanacyclopropane with additional titanium(IV) isopropoxide to afford 2 equivalents of titanium(III) isopropoxide (Kulinkovich, Synlett 2004, 77.DOI). This non-productive side reaction reaches a maximum as the ratio of titanium(IV) isopropoxide to EtMgBr approaches a stoichiometry ,stkmtr of 1:1. However, this sequence can be useful for the generation of low valent titanium compounds that can be utilized for example inPinacol频哪醇Coupling Reactions.The reaction of higher alkylmagnesium halides (e.g. PrMgX) leads to products with two stereocenters, and high diastereoselectivity can be had in the absence of any chelating螯合substituents in the substrate:For this reason, the reaction is also applicable to the synthesis of higher substituted cyclopropanols.The disproportion aspect of the mechanism means that only one of the two organomagnesium ligands is incorporated into the reaction product, which is a concern when the Grignard reagent used is not a commercial item. Two interesting modifications help to improve the atom economy for more specialized ligands.One method is to use a terminal alkene that can undergo a ligand exchange. The exchange is fast for styrenes苯乙烯, and allows the use of EtMgBr as the Grignard reagent. For other terminal alkenes, the bulkier cyclohexylmagnesium halides can be be used to retard the participation of the initially formed titanium(II) species in the alkylation reaction and to promote the reaction of the desired ligand with the ester. Sub-stoichiometric amounts of titanium(IV) isopropoxide can still be used in this ligand exchange modification.In the other modified procedure, described by de Meijere, MeTi(OiPr)3 is formed first, and a stoichiometric amount is used with only 1.1 eq. of a Grignard Reagent. Here, the disproportionation produces methane as a gaseous side product and allows the Grignard reagent to be fully utilized:For more on the topic of 1,n-dicarbanionic titanium intermediates from monocarbanionic organometallics and their application in organic synthesis, see a recent review by Kulinkovich and de Meijere (Chem. Rev. 2000, 100, 2789. DOI)Some years after the development of the Kulinkovich Reaction, a highly versatile preparation of cyclopropylamines from amides was worked out byde Meijere and a conversion of nitriles into primary cyclopropylamines was developed bySzymoniak.Recent LiteratureTitanium(IV) Isopropoxide-Catalyzed Formation of 1-Substituted Cyclopropanols in the Reaction of Ethylmagnesium Bromide with Methyl Alkanecarboxy