Expeditious Synthesis of 2-Aryl Substituted Imidazolines and Imidazoles

A versatile and efficient method for the synthesis of 2-aryl substituted imidazolines and imidazoles bearing a carboxylate group on C-4 is reported.Three different synthetic pathways were explored, compared and optimized.The selected procedure involves condensation of methyl 2,3-diaminopropionate with different imino ethers.The ring closure, monitored by LC-MS analysis, was facilitated by heating at reflux in ethanol leading to increase the rate of cyclization.1,3-Oxazole, thiazole and imidazole derivatives are the subjects of intensive research.These heterocycles mimicking amide bond can be viewed as natural conformationally constrained unusual peptides which could counteract problems that limit clinical applications 1-4 of peptides such as : (i) rapid degradation by many specific or nonspecific peptidases under physiological conditions ; (ii) conformational flexibility which allows a peptide to bind to more than one receptor or receptor subtype ; (iii) poor absorption and transportation.In addition these heterocycles constitute excellent chelating agents able to bind to many metalloenzymes.A large number of strategies have also employed imidazoline and imidazole to develop original compounds.For example, these heterocycles were introduced in the design of farnesyl protein transferase inhibitors such as Zarnestra 5 or new efficient non peptidic medicinal compounds. 6Moreover, the replacement of amino acids by heterocyclic groups has been used in the design of AT 1 angiotensin II antagonists such as Losartan 7 or Irbesartan 8 and analogues 9,10 (Scheme 1).