Synthesis of Substituted 2-Aminoimidazoles

Key words

2-aminoimidazoles - cyanamides - hydroamination - lanthanum(III)

Significance

Looper and co-workers described a three-step synthesis of highly substituted 2-aminoimidazoles. The first step consists of the preparation of propargyl cyanamides by copper(I)-­catalyzed addition of an iminium generated from condensation of aldehydes (R^² = alkyl or aryl) with secondary amines. Without further purification, the resulting tertiary amines are subjected to a von Braun reaction. The use of 4-methoxybenzyl-, 2,4- and 3,4-dimethoxybenzyl-substituted propargyl amines lead to the propargyl cyanamides in good yields whereas symmetric N,N-dialkylpropargyl amines give exclusively propargyl bromide. Screening of catalysts led to the use of La(OTf)₃ for the final addition-hydroamination step. Both acyclic and cyclic secondary amines generated guanidine intermediates which underwent cyclization to the alkyne to afford 2-aminoimidazoles in good yields.

Comment

Several alkaloids containing the 2-aminoimidazole ring with interesting structures and biological properties have been isolated from marine sponges (S. M. Weinreb Nat. Prod. Rep. 2007, 24, 931).This scaffold improves physicochemical properties like lipophilicity, blood-brain barrier passage, cell permeability and bioavailability. Polysubstituted 2-aminoimidazole synthesis remains challenging as the current methods present some disadvantages: i) use of unstable precursors for the condensation of α-amino/α-­haloketone with a cyanamide or a guanidine derivative respectively; ii) multi-step synthesis for the decoration of the imidazole scaffold. This three-step sequence represents a useful tool for the ­efficient synthesis of diversely substituted
2-aminoimidazoles from readily available starting materials.