Kulinkovich-de Meijere Reaction

The Kulinkovich-de Meijere Reaction is a modification of the Kulinkovich Reaction that allows the preparation of cyclopropylamines by the reaction of Grignard reagents (substituted ethylmagnesium halides) with N,N-dialkylamides and dialkylformamides in the presence of a stoichiometric amount of titanium(IV) isopropoxide or, even better, methyltitanium triisopropoxide.

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Mechanism of the Kulinkovich-de Meijere 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.

An oxatitanacyclopentane intermediate is initially formed by insertion of the carbonyl group of the amide into the titanium-carbon bond of the titanacyclopropane. Due to the poor leaving group ability of the dialkylamino group, this oxatitanacyclopentane does not undergo ring contraction as does the corresponding oxatitanacyclopentane from an ester (Kulinkovich Reaction), but rather ring opening to an iminium-titanium oxide inner salt takes place, and the resulting intermediate cyclizes to the cyclopropylamine:

Although the use of sub-stoichiometric amounts of the titanium reagent is possible, yields are significantly better with stoichiometric amounts. High yields are obtained from N,N-dialkylformamides, whereas amides with bulky groups consistently give products in lower yield. Improved yields can be obtained by using methyltitanium triisopropoxide as well as by adding the Grignard reagent to the mixture of the amide and the titanium reagent at ambient instead of low temperature.

If the Grignard reagent is valuable, only one equivalent is required when methyltitanium triisopropoxide is used. In addition, when the titanacyclopropane intermediate is prepared from cyclohexyl or cyclopentyl magnesium halide, ligand exchange with various alkenes (mono-, disubstituted, and cycloalkenes) can be employed to expand the range of accessible products. The combination of both methods offers a broad synthetic potential for the synthesis of new cyclopropylamines:

A modification by Szymoniak allows the preparation of primary cyclopropylamines by the reaction of nitriles with Grignard reagents in the presence of titanium tetraisopropoxide and a Lewis acid.

A recent review by de Meijere (J. Organomet. Chem. 2004, 689, 2033. DOI) describes the full scope of titanium-mediated syntheses of cyclopropylamines.

Recent Literature

Mono- and Disubstituted N,N-Dialkylcyclopropylamines from Dialkylformamides via Ligand-Exchanged Titanium-Alkene Complexes
A. de Meijere, C. M. Williams, A. Kourdioukov, S. V. Sviridov, V. Chaplinski, M. Kordes, A. I. Savchenko, C. Stratmann, M. Noltemeyer, Chem. Eur. J., 2002, 3789-3801.

The Kulinkovich Reaction in the Synthesis of Constrained N,N-Dialkyl Neurotransmitter Analogues
C. A. Faler, M. M. Joullié, Org. Lett., 2007, 9, 1987-1990.