Van Leusen Imidazole Synthesis
Van Leusen Three-Component Reaction (vL-3CR)
The Van Leusen Imidazole Synthesis allows the preparation of imidazoles from aldimines by reaction with tosylmethyl isocyanide (TosMIC). The reaction has later been expanded to a two-step synthesis in which the aldimine is generated in situ: the Van Leusen Three-Component Reaction (vL-3CR).
Mechanism of the Van Leusen Imidazole Synthesis
The mechanism according to a publication by Van Leusen (J. Org. Chem., 1977, 42, 1153-1159. Abstract) is driven by TosMIC, which contains a reactive isocyanide carbon, an active methylene group and a leaving group.
The CH2N=C moiety can undergo a stepwise cycloaddition to a polarized double bond under basic conditions.
Elimination of p-toluenesulfinic acid (TosH) from the intermediate 4-tosyl-2-imidazoline provides a 1,5-disubstituted imidazole::
The aldimine can also be generated in situ by condensation of an amine with an aldehyde in approximately half an hour. The water formed as a byproduct does not interfere with the cycloaddition, and addition of drying reagents such as MgSO4 is not needed. However, despite the name, the vL-3CR is not a true multicomponent reaction, as the components react stepwise. Otherwise, in the absence of the initial imine formation, the reaction of aldehydes with TosMIC leads to oxazoles.
Chemistry of sulfonylmethyl isocyanides. 12. Base-induced cycloaddition of sulfonylmethyl isocyanides to carbon,nitrogen double bonds. Synthesis of 1,5-disubstituted and 1,4,5-trisubstituted imidazoles from aldimines and imidoyl chlorides
A. M. Van Leusen, J. Wildeman, O. H. Oldenziel, J. Org. Chem., 1977, 42, 1153-1159.
Fused bicyclic imidazole rings have been prepared in good yields by a sequence of the van Leusen three-component reaction and the ring-closing metathesis reaction.
V. Gracias, A. F. Gasiecki, S. W. Djuric, Org. Lett., 2005, 7, 3183-3186.