An Optimized Process for Formation of 2,4-Disubstituted Imidazoles from Condensation of Amidines and α-Haloketones

Abstract

The preparation of 2,4-disubstituted imidazoles from the condensation of α-haloketones with amidines is described. The optimal reaction protocol is to add the α-bromoketone solution to the amidine in aqueous tetrahydrofuran in the presence of potassium bicarbonate under vigorous reflux. Imidazole was isolated in 83−91% yield with >95% purity without column chromatography.

Base‐Mediated Syntheses of Di‐ and Trisubstituted Imidazoles from Amidine Hydrochlorides and Bromoacetylenes

“…In light of these results and based on literature precedence,19, 21, 22, 25 we considered two possible reaction pathways (Scheme ); either a base‐mediated addition of the amidine to the bromoacetylene took place, affording intermediates 4 and 4′ , which, upon cyclization, led to the observed imidazole 3 (path A), or, alternatively, bromoacetylene 2 hydrolyzed affording a highly reactive 2‐bromoketone 5 , which, by reacting with the amidine, resulted in the formation of the isolated product 3 (path B). This pathway would easily explain the experimentally observed important role of water needed to achieve a high product yield.…”

Current advances in the synthesis and biological potencies of tri- and tetra-substituted 1H-imidazoles

“…In general, 2,4,5-tri-substituted imidazoles are synthesized via a three-component cyclo-condensation of 1,2-diketone or α-hydroxyketone or α-ketomonoxime with an appropriate aldehyde and ammonium acetate. The appropriate 1,2-dicarbonyl compounds, aldehydes and ammonia, were used by Japp and Radziszewski successfully to synthesize the first imidazole core to yield 2,4,5-triphenylimidazoles 108 back in 1882 (Scheme 27) [73][74][75][76].…”

4-(4-Fluorophenyl)-1-methoxymethyl-2-phenyl-1H-imidazole

“…For the preparation of diarylimidazoles, see: Li et al (2002). For synthesis of and with related diarylimidazoles, see: Liverton et al (1999); Kawasaki et al (1996).…”