Kulinkovich cyclopropanation

The versatile Ti(II) chemistry available using preformed (alkene)Ti(OiPr)2 species was opened up by the discovery of the Kulinkovich cyclopropanation reaction [55]. Since 1995, Sato and collaborators have developed a wide range of elegant and synthetically useful reactions based on the Ti(OiPr)4/iPrMgCl reagent [56]. In particular, it was reported that the Ti(II) complex (q2-propene)Ti(OiPr)2, preformed from Ti(OiPr)4 and 2 equivalents of iPrMgCl, reacts with allylic compounds, such as halide, acetate, carbonate, phosphate, sulfonate, and aryl ether derivatives, to afford allyltitanium compounds as depicted in Scheme 13.27 [57]. 

Indoline and proline derivatives 150 and 151, on treatment with r-HexMgBr and MeTi(0-/-Pr)3, underwent the intramolecular Kulinkovich cyclopropanation leading to annelated pyrrolizines 152 and 153, respectively, as mixtures of cis- and /raar-diastereomers (Scheme 30) <2004CEJ785>. 

Intra- and Intermolecular Kulinkovich Cyclopropanation Reactions of Carboxylic Esters with Olefins. 

An intramolecular Kulinkovich cyclopropanation of an oxa-tu-alkenoic ester 433 occurs upon treatment with cyclohexyl magnesium chloride to furnish the cyclopropanochroman-3-ol 434 in moderate yield (Equation 179) <20030BC3600>. 

INTRA- AND INTERMOLECULAR KULINKOVICH CYCLOPROPANATION REACTIONS OF CARBOXYLIC ESTERS WITH OLEFINS BICYCLO[3.1.0]HEXAN-1-OL AND trans-2-BENZYL-l-METHYLCYCLOPROPAN-l-OL... 

The Kulinkovich cyclopropanation, in which an ester and two equivalents of a Grignard reagent are combined to make a cyclopropanol in the presence of a catalytic amount of Cp2TiCl2, is a useful variant of reductive coupling reactions. A cyclopropylamine can be obtained instead if a tertiary amide is substituted for the ester. 

Problem 6.12. Write a reasonable mechanism for the following Kulinkovich cyclopropanation ... 

Kulinkovich Cyclopropanation. The Kulinkovich method produced cyclopropanols from carboxylic acid esters and ethylmagnesium bromide in the presence of catal3d ic amount of titanium tetraisopropoxide (Scheme 4). The intermediate was proposed to involve titanacyclopropane. Generally, good to excellent yields were observed for 1-alkylcyclopropanols (55). 1,2-Disubstituted cyclo-... 

Kulinkovich cyclopropanol synthesis, also known as Kulinkovich reaction or Kulinkovich cyclopropanation, is titanium-catalyzed transformation of esters... 

Kulinkovich himself proposed that the dialkoxytitanacyclopropanes as the key intermediate in the Kulinkovich cyclopropanation. Extensive theoretical study on mechanism was published in 2001. Eisch also provided detailed exploration of the mechanism for the Kulinkovich reaction in 2003. In 2007, Kulinkovich proposed a modified ate complex mechanism for titanium-mediated cyclopropanation of carboxylic esters with Grignard reagents. 

Intramolecular Kulinkovich cyclopropanation reaction of carboxylic ester with olefin bicycio[3.1.0)hexan-l-ol (2) ... 

Intermolecular Kulinkovich cyclopropanation reaction of carboxylic ester with olefin ... 

In fact, only in some cases are real carbenoid species involved in these reactions. The reactions employing oxophilic metals such as Zn, Fe, Sm, and In were reported [9], and representative examples are given in Scheme 3. Such reactions exhibit obvious synthetic limitations, since only aromatic (unsaturated) carbonyl compounds can be used, and/or cyclopropanes of a very specific structure obtained. The Kulinkovich and related reactions, involving dianion equivalents (1, Scheme 1), represent the only synthetically useful deoxygenative process at present. 

In this context, zirconium chemistry could open up new prospects for developing deoxygenative approaches to cyclopropanes. The Zr-assisted variant of the Kulinkovich reaction has been reported (Scheme 4, Eq. 1) [10]. Cyclopropanols were also formed, as by-products in addition to homoallylic alcohols, from aliphatic acid chlorides (Eq. 2) [ 10]. The conversion of acid chlorides (and also esters in several cases) into the corresponding homoallylic alcohols... 

The synthesis of cyclopropanes from carbonyl compounds represents a new approach for converting zirconacycles into carbocycles via a deoxygenative ring contraction under Lewis acid activation. It differs in that from the spontaneous Kulinkovich process. Further progress would involve extension to the synthesis of 1,2-substituted cyclopropanes and the development of catalytic and enantioselective variants. 

Epstein, O. L., Savchenko, A. I., Kulinkovich, O. G. On the mechanism of titanium-catalyzed cyclopropanation of esters with aliphatic organomagnesium compounds. Deuterium distribution in the reaction products of (CD3)2CHMgBr with ethyl 3-chloropropionate in the presence of titanium tetraisopropoxide. Russ. Chem. Bull. 2000, 49, 378-380. 

Cyclopropane derivatives. The intramolecular Kulinkovich reaction of 2-substituted 5-hexenoyl bomanesultams is a useful method for the synthesis of chiral endo-2-substituted bicyclo[3.1.0]hexan-l-ols. Extension of the reaction scope to amides results in the formation of cyclopropylamines and cyclopropylstannanes. ... 

Functionalized cyclopropanes. The reductive coupling of esters with 1-alkenes by a Grignard reagent and titanium alkoxide gives rise to cyclopropanols (the Kulinkovich reaction). With the use of ethylene carbonate, the condensation gives rise to 2-substituted cyclopropanone hemiacetals. An intramolecular version delivers bicyclic products. ... 

Cyclopropanation of olefins with diazomethane Darzens condensation Jacobsen epoxidation—additive oxidation Kulinkovich reaction... 

The other significant variation of the prototypical Kulinkovich reaction is the so-called Kulinkovich-de Meijere reaction, where de Meijere extended the substrates from esters to amides. Other carboxylic acid derivatives including (cyclic) carbonate, imides, and nitriles also react with the key Kulinkovich intermediate. Szymoniak developed an efficient new synthesis of cyclopropanes via hydrozirconation of allylic ethers (e.g., using Cp2Zr(H)Cl) followed by addition of a Lewis acid (e.g., BFa OEta). Casey et al. further investigated the stereochemistry of this interesting cyclopropanation reaction using deuterated allylic ethers. ... 

Amides can also be employed as substrates. The mechanism in this case is subtly different to the mechanism involving the ester (Schemes 5.82-5.84). If the mechanism were the same, the amino group would be eliminated and the same product would be obtained. Instead, as with the LiAULr reduction of amides, the oxo group is eliminated, and the amino group is retained in the product, which is an amino cyclopropane 5.313. As with the esters, intramolecular Kulinkovich reactions are also possible (Schemes 5.85 and 5.86). ... 

Scheme 2-82. Synthesis of cyclopropanes from alkylmagnesium halides (Kulinkovich...

The Kulinkovich reaction is a unique reaction, in which cyclopropane derivatives are formed by a reaction between titanacyclopropanes and ester derivatives. The reaction was established by Kulinkovich in 1989 [273], and a recent review has been published [274, 275], Titanacyclopropanes were generated from a Grignard reagent and Ti(0-/-Pr)4, and the reaction with esters gave cyclopropanol in good yields. When amides are used instead, cyclopropane amine is formed. The mechanistic study on the Kulinkovich reaction was performed [276]. 

Activated methylene cyclopropane was prepared by de Meijere s group using Kulinkovich s method (Scheme... 

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