Kulinkovich cyclopropanation

What is Kulinkovich cyclopropanation?

The Kulinkovich reaction, first reported in 1989 by Kulinkovich et al., is a method for synthesizing cis-1,2-dialkylcyclopropan-1-ol from carboxylic acid esters using Grignard reagent and a catalytic or equivalent amount of titanium tetraisopropoxide Ti(O-i-Pr)4. It is also known as the Kulinkovich cyclopropanation, Kulinkovich hydroxycyclopropanation, Kulinkovich-de Meijere reaction, or Kulinkovich cyclopropanol synthesis.

Kulinkovich cyclopropanation - general reaction scheme- Kulinkovich hydroxycyclopropanation - Kulinkovich-de Meijere reaction - Kulinkovich cyclopropanol synthesis
Kulinkovich cyclopropanation

This reaction involves the formation of a low-valency dialkoxytitanacyclopropane intermediate and is known to give intrinsically cis-1,2-dialkyl diastereoselectivity without chelating substituents on the substrates, regardless of the size of the substituent. Additionally, the stereochemistry at the carbon bound to titanium is retained. As a result, this reaction has been applied to various substrates such as amides, nitriles, lactones, THP-protected hydroxy esters, and vinylogous esters.

The Kulinkovich reaction has also been modified to be asymmetric by using the chiral ligand TADDOL. Other modifications include the addition of Grignard reagent to amides in the presence of methyltitanium triisopropoxide and the catalytic version of this reaction initiated by the ligand-exchange reaction of Grignard reagent and titanium tetraisopropoxide.

The application of Kulinkovich reaction has been extended to the synthesis of not only cyclopropanols but also other noncyclopropyl products.

References

Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A. and Pritytskaya, T. S., Zh. Org. Khim., 1989, 25, 2244.

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