Titanium-mediated syntheses of cyclopropylamines

Abstract

The transformations of N, N-dialkylcarboxamides and nitriles with 1,2-dicarbanionic organometallics in situ generated from organomagnesium (Grignard) as well as organozinc reagents in the presence of stoichiometric or substoichiometric (semi-catalytic) quantities of a titanium alkoxide derivative of type XTi(OR) 3 with X=OR, Cl, Me and OR=O iPr, OEt are described. The key step in the transformation of a monocarbanionic into a 1,2-dicarbanionic organotitanium species is a disproportionation of a dialkyltitanium intermediate to form an alkane and a titanium alkene complex which has the reactivity of a titanacyclopropane derivative. The latter are able to undergo insertion of the carbonyl group of an N, N-dialkylcarboxamide or a cyano group to furnish, after ring contraction and hydrolysis, dialkylcyclopropylamines or cyclopropylamines, respectively. The titanium alkene complexes can also undergo ligand exchange with alkenes to afford new titanacyclopropanes, which subsequently react as 1,2-dicarbanionic equivalents. In many cases, these titanium-mediated formations of a wide range of synthetically and/or pharmacologically important cyclopropylamines proceed in good to very good yields (from 20% to 98% for dialkylcyclopropylamines from N, N-dialkylcarboxamides and from 27% to 73% for primary cyclopropylamines from nitriles) and with high chemo- and stereoselectivity. These circumstances in conjunction with the simplicity of the experimental handling and inexpensiveness of the reagents favor these reactions for an ever increasing range of applications in organic synthesis.