Kulinkovich-Szymoniak Reaction

The Kulinkovich-Szymoniak Reaction is a modification of the Kulinkovich Reaction that allows the preparation of primary cyclopropylamines by the reaction of Grignard reagents (substituted ethylmagnesium halides) with nitriles in the presence of a stoichiometric amount of titanium(IV) isopropoxide, and exposure to a Lewis acid in a subsequent step.

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Mechanism of the Kulinkovich-Szymoniak 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.

Under Kulinkovich-de Meijere conditions, the reaction of nitriles with the titanacyclopropane gives predominantly ketones, whereas Lewis acid activation efficiently converts the azatitanacycle into the corresponding cyclopropylamine.

When using more than two equivalents of EtMgBr, the yield of the cyclopropylamine decreases in favor of a tertiary carbinamine. The use of sub-stoichiometric amounts of titanium(IV) isopropoxide also decreases the yield of the cyclopropylamine, while increasing the yield of carbinamine and ketone.

The use of substituted Grignard Reagents (R > Et) leads to 1,2-disubstituted cyclopropylamines with moderate diastereoselectivity (~2:1), but flash chromatography allows the easy separation of a specific diastereomer.

P. Bertus, J. Szymoniak, Chem. Commun., 2001, 1792-1793.

The titanium-mediated synthesis of primary cyclopropylamines from nitriles and Grignard reagents has been reviewed in detail by Szymoniak and Bertus (Synlett 2007, 1346. DOI)

Recent Literature

New and easy route to primary cyclopropylamines from nitriles
P. Bertus, J. Szymoniak, Chem. Commun., 2001, 1792-1793.

Primary 1-Arylcyclopropylamines from Aryl Cyanides with Diethylzinc and Titanium Alkoxides
S. Wiedemann, D. Frank, H. Winsel, A. de Meijere, Org. Lett., 2003, 5, 753-755.

A Direct Synthesis of 1-Aryl- and 1-Alkenylcyclopropylamines from Aryl and Alkenyl Nitriles
P. Bertus, J. Szymoniak, J. Org. Chem., 2003, 68, 7133-7136.