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The Kulinkovich reaction describes the organic synthesis of cyclopropanols via reaction of esters with dialkyldialkoxytitanium reagents, generated in situ from Grignard reagents bearing hydrogen in beta-position and titanium(IV) alkoxides such as titanium isopropoxide. This reaction was discovered by Oleg Kulinkovich and coworkers in 1989. The titanium reagent can be used catalytically.
Contents
Titanium catalysts are ClTi(OiPr)3 or Ti(OiPr)4, ClTi(OtBu)3 or Ti(OtBu)4, Grignard reagents are EtMgX, PrMgX or BuMgX. Solvents can be Et2O, THF, Toluol. Tolerated Functional Groups: Ethers R–O–R, R–S–R, Imines RN=CHR. Amides, primary and secondary amines, most carbamates are not stable to the reaction conditions, but tert-butyl carbamates (N-Boc derivatives) survive the transformation.
An asymmetric version of this reaction is also known with a TADDOL-based catalyst.
Reaction mechanism
The generally accepted reaction mechanism initially utilizes two successive stages of transmetallation of the committed Grignard reagent, leading to an intermediate dialkyldiisopropyloxytitanium complex. This complex undergoes a dismutation to give an alkane molecule and a titanacyclopropane 1. The insertion of the carbonyl group of the ester in the weakest carbon-titanium bond leads to an oxatitanacyclopentane 2 being rearranged to ketone 3. Lastly, the insertion of the carbonyl group of 3 in the residual carbon-titanium connection forms a cyclopropane ring. In the transition state of this elementary stage, which is the limiting stage of the reaction, an agostic interaction stabilizing between the beta hydrogen and the R2 group and the titanium atom was called upon to explain the diastereoselectivity observed. Complex 4 obtained is a tetraalkyloxytitanium compound able to play a part similar to that of the starting tetraisopropyloxytitanate, which closes the catalytic cycle. At the end of the reaction, the product is mainly in the shape of the magnesium alcoholate 5, giving the cyclopropanol after hydrolysis by the reaction medium.
The reaction mechanism of the Kulinkovich reaction was the subject of thorough calculations published in 2001. Certain points remain nevertheless obscure and the mechanism of this reaction is actually not so simple. Intermediate titanium complexes of the ate type were recently proposed by Kulinkovich.
Ligand exchange with olefins
In 1993, the team of Kulinkovich highlighted the aptitude of the titanacyclopropanes to undergo ligand exchange with olefins. This discovery was important, because it gave access to cyclopropanols more functionalized by making economic use of the Grignard of which normally at least two equivalents should have been engaged to obtain good outputs. Cha and its team introduced the use of cyclic Grignard reagents, particularly adapted for these reactions.
The methodology has been extended to intramolecular reactions
de Meijere variation
With amides instead of esters the reaction product is an aminocyclopropane in the de Meijere variation
The intramolecular reaction is also known:
Szymoniak variation
In the Szymoniak variation the substrate is a nitrile and the reaction product a cyclopropane with a primary amine group.
The reaction mechanism is akin the Kulinkovich reaction: