Everything about The Kulinkovich Reaction totally explained
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. Reaction was found by Kulinkovich and coworkers in 1989 . Titanium reagent could be used catalytically.
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 Et
2O, THF, Toluol. Tolerated
Functional Groups:
Ethers R-O-R, R-S-R,
Imines RN=CHR.
Amides, primary and secondary
amines,
carbamates are not stable to the reaction condition
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
organomagnesium compound, 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 a 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 a 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:
» Further Information
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