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.
Mechanism of the Kulinkovich Reaction
If 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 β-hydride elimination with the loss of ethane to yield the substituted titanacyclopropane:
The titanacyclopropane reacts with the ester as a 1,2-dicarbanion equivalent to produce a cyclopropanol after a 2-fold alkylation:
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 of 1:1. However, this sequence can be useful for the generation of low valent titanium compounds that can be utilized for example in Pinacol 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 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, 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 by de Meijere and a conversion of nitriles into primary cyclopropylamines was developed by Szymoniak.
Titanium(IV) Isopropoxide-Catalyzed Formation of 1-Substituted Cyclopropanols in the Reaction of Ethylmagnesium Bromide with Methyl Alkanecarboxylates
O. G. Kulinkovich, S. V. Sviridov, D. A. Vasilevski, Synthesis, 1991, 234.