Kulinkovich cyclopropanation refers to the reaction of esters, amides, and other carboxylic acid derivatives with Grignard reagents containing. Kulinkovich reaction: a facile method for cyclopropanol synthesis from esters Computational Study on Selectivity of Kulinkovich Reaction. An intermolecular Ti(IV)-mediated cyclopropanation reaction has been used to synthesize substituted 2-phenylcyclopropylamines and constrained analogues of .
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The successful use in the synthesis of natural compounds is outlined in this perspective.
In the other modified procedure, described by de Meijere, MeTi O i Pr 3 is formed first, and a stoichiometric amount is used with only 1. Although 2 is prepared from methylmagnesium bromide, only one equivalent of Grignard reagent is needed for the Kulinkovich reaction raction methane evolves as the reaction proceeds Eq.
The reaction of higher alkylmagnesium halides e. Navigation menu Personal tools Log in. A 1 M solution of n -butylmagnesium chloride in ether 52 mL, 52 mmol is added over a period of 6. Search articles by author Isabell Haym.
It should be noted that an anionic catalytic cycle involving a series of catalytic ate complexes has been proposed to explain the need for more than two equivalents of Grignard reagent under conditions that employ stoichiometric amounts of titanium. Back to tab navigation. Significant 1,3-stereocontrol is also observed when chiral homoallylic alcohols are employed Eq.
A cis relationship between substituents on the 1- and 2-positions of the cyclopropanol product is often observed in these reactions. The use of bulky Grignard reagents can lower the yields of Kulinkovich reactions. Complex 4 obtained is a tetraalkyloxytitanium compound able to play a part similar to that of the starting tetraisopropyloxytitanate, which closes the catalytic cycle. Formation of the more stable monosubstituted titanancyclopropane from the disubstituted intermediate derived from cyclohexylmagnesium chloride drives the formation of the less substituted product Eq.
The generally accepted reaction mechanism initially utilizes two successive stages of transmetallation of the committed Grignard reagentleading to an intermediate dialkyldiisopropyloxytitanium complex. Site Search any all words. Titanium II is reoxidized to titanium IV over the course of this addition process.
Previous Article Next Article. For example, the final step in Eq. The bonds between the hydroxyl-bearing carbon of a cyclopropanol and the other ring carbons are susceptible to cleavage in the presence of electrophiles or acids. Stereoselective construction of bicyclo[5.
The Kulinkovich hydroxycyclopropanation reaction in natural product synthesis I. In other projects Wikimedia Commons.
The exchange is fast for styrenes, and allows the use of EtMgBr as the Grignard reagent. Carbon-carbon bond forming reactions Titanium Name reactions. Enantioselective versions of the Kulinkovich reaction are rare, and enantioselectivities are moderate. The step that establishes the relative configuration of the product is the second migratory insertion of the carbonyl group into the titanium-carbon bond.
In all cases the Ref. XX is the XXth reference in the list of references. Journal of the American Chemical Society. Contrary to the typical cis diastereoselectivity of the reaction, homoallylic alcohols may be cyclopropanated to afford trans -1,2-dialkylcyclopropanols. Go to our Instructions for using Copyright Clearance Center page for details.
Despite the possibility of olefin exchange with the titanacyclopropane intermediate see Eq. For example, samarium-mediated reductive ring closure provides cyclopropanols in high yield Eq. A recent review by de Meijere J.
A titanacyclopropane intermediate is common to all Kulinkovich-type cyclopropanations. The trans -1,2-dialkylcyclopropanol is favored under these conditions.
Cyclopropanation of carbonates provides access to synthetically useful cyclopropanone hemiacetals Eq. Crystallographic evidence indicates a carbon-carbon bond length between those of typical single and double bonds, and partial pyramidalization of the carbon atoms.
The presence of an alcohol in the target means that ketones may be used as electrophiles for intramolecular ring closing to form cyclopropanols. Due to the poor leaving group ability of the dialkylamino group, this oxatitanacyclopentane does not undergo ring contraction as does the corresponding oxatitanacyclopentane from an ester Kulinkovich Reactionbut rather ring opening to an iminium-titanium oxide inner salt takes place, and the resulting intermediate cyclizes to the cyclopropylamine:.
The combination of both methods offers a broad synthetic potential for the synthesis of new cyclopropylamines:. Improved yields can be obtained by using methyltitanium triisopropoxide as well as by adding the Grignard reagent to the mixture of the amide and the titanium reagent at ambient instead of low temperature.
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. Jump to site search. If the Grignard reagent is valuable, only one equivalent is required when methyltitanium triisopropoxide is used. In addition, the reaction may be carried out in the presence of either a full equivalent or substoichiometric amount of titanium reagent, and the titanium reagent may be varied somewhat to optimize yields.
Complex VIa leads to the observed major cis diastereomer and is more favorable than the diastereomeric VIb due to unfavorable steric interactions between R and Ti OY 3 in the latter Eq. The use of a syringe pump is advised when slow addition of the Grignard reagent is required. 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.
In addition, when the titanacyclopropane intermediate is prepared from cyclohexyl or cyclopentyl magnesium halide, ligand exchange with various alkenes mono- disubstituted, and cycloalkenes can be employed to expand the range of kulnikovich products. The reaction mechanism of the Kulinkovich reaction was the subject of thorough calculations published in When Fischer carbenes are used, the reaction proceeds through a chair-like transition state Eq.
Some years after the development of the Kulinkovich Reaction, a highly versatile preparation of cyclopropylamines from amides was worked out by kulinkovih Meijere and a conversion of nitriles into primary cyclopropylamines was developed by Szymoniak.
For reproduction of material from PPS: The methodology has been extended to intramolecular reactions . One method is to use a terminal alkene that can undergo a ligand exchange.