KULINKOVICH REACTION PDF

Synthesis of amines Kulinkovich-Szymoniak Reaction The Kulinkovich-Szymoniak Reaction is a modification of the Kulinkovich Reaction that allows the preparation of primary cyclopropylamines by the reaction of Grignard reagents substituted ethylmagnesium halides with nitriles in the presence of a stoichiometric amount of titanium IV isopropoxide, and exposure to a Lewis acid in a subsequent step. Mechanism of the Kulinkovich-Szymoniak Reaction The formation of the initial titanacyclopropane intermediate from the Grignard reagent and the titanium IV isopropoxide has already been described in the article on the Kulinkovich Reaction. Under Kulinkovich-de Meijere conditions, the reaction of nitriles with the titanacyclopropane gives predominantly ketones, whereas Lewis acid activation efficiently converts the azatitanacycle into the corresponding cyclopropylamine. When using more than two equivalents of EtMgBr, the yield of the cyclopropylamine decreases in favor of a tertiary carbinamine. The use of sub-stoichiometric amounts of titanium IV isopropoxide also decreases the yield of the cyclopropylamine, while increasing the yield of carbinamine and ketone.

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The original Kulinkovich reaction discovered in employed esters and ethyl Grignard and yielded mono- or disubstituted cyclopropanols Eq. Additionally, an olefin exchange process introduced in has enlarged the scope of possible products to include more highly substituted cyclopropanols.

Despite some operational difficulties associated with the need to slowly introduce the Grignard reagent, the Kulinkovich reaction employs readily available reagents and provides access to synthetically useful cyclopropanols. 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. Mechanism and Stereochemistry Prevaling Mechanism The mechanism of the prototypical Kulinkovich cyclopropanation begins with the displacement of alkoxides on titanium by two equivalents of Grignard reagent to form intermediate I.

This intermediate may be depicted using either the titanacyclopropane resonance structure IIa or the titanium II -olefin structure IIb. Crystallographic evidence indicates a carbon-carbon bond length between those of typical single and double bonds, and partial pyramidalization of the carbon atoms.

Displacement of the product by two more equivalents of Grignard reagent restarts the catalytic cycle Eq. These pathways have not yet been distinguished experimentally. The step that establishes the relative configuration of the product is the second migratory insertion of the carbonyl group into the titanium-carbon bond.

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.

When R1 is bulky, the trans isomer is favored. Despite the possibility of olefin exchange with the titanacyclopropane intermediate see Eq. This drawback seems to limit the scope of the reaction significantly; however, it is possible for the intermediate titanacycle II to exchange with a more substituted olefin to afford more highly substituted cyclopropanols in high yield Eq.

Formation of the more stable monosubstituted titanancyclopropane from the disubstituted intermediate derived from cyclohexylmagnesium chloride drives the formation of the less substituted product Eq. Although 2 is prepared from methylmagnesium bromide, only one equivalent of Grignard reagent is needed for the Kulinkovich reaction because methane evolves as the reaction proceeds Eq. Significant 1,3-stereocontrol is also observed when chiral homoallylic alcohols are employed Eq.

For instance, amides may be cyclopropanated to afford cyclopropylamines in high yield and diastereoselectivity Eq. The trans-1,2-dialkylcyclopropanol is favored under these conditions. This result is a consequence of inversion of configuration at the carbon bound to titanium in the second migratory insertion step when amides are employed contrast with Eq.

This mode of reactivity has made cyclopropanols synthetically useful; for instance, they may serve as homoenolate equivalents in the presence of an electrophile. When the electrophile is part of the cyclopropanol, ring expansion may result Eq.

The results of reactions of this type are often sensitive to the nature of the electrophile and other reagents employed. They may serve as iminium ion equivalents in the presence of a nucleophile. For example, the final step in Eq. The presence of an alcohol in the target means that ketones may be used as electrophiles for intramolecular ring closing to form cyclopropanols.

For example, samarium-mediated reductive ring closure provides cyclopropanols in high yield Eq. When Fischer carbenes are used, the reaction proceeds through a chair-like transition state Eq. The use of a syringe pump is advised when slow addition of the Grignard reagent is required. Example Procedure [20] 18 To a mL, round-bottomed flask, equipped with a magnetic stirring bar and rubber septum, is added at room temperature a mixture of 2.

A 1 M solution of n-butylmagnesium chloride in ether 52 mL, 52 mmol is added over a period of 6. After the addition is complete, the resulting black reaction mixture is stirred for an additional 20 min. The resulting mixture is stirred for an additional 3 h at room temperature. Dissertation, Belarusian State University, Minsk, Tetrahedron , 52,

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