Synthesis of 2-Arylsubstituted Imidazolone Derivatives

Abstract

Since imidazolones have been found to be associated with their various biological activities such as potassium channel opener, phosphodiesterase III/IV inhibition, and crop protection, this class of compounds has become a synthetic target for organic and medicinal chemists. Due to increased interest, several synthetic approaches of these compounds have been investigated via solution or solid-phase synthesis. Among imidazolones, 2-aminoimidazolone containing the guanidine moiety is particularly an attractive scaffold due to its hydrogen bonding donor and acceptor abilities in the active sites of various proteins. 2-Aminoimidazolones (i-v) synthesized up to date are shown in Figure 1 and they exhibit various biological activities. Based on this finding, we decided to synthesize new imidazolone derivatives (vi) bearing carbon instead of nitrogen at 2-position expecting that compound vi would offer different chemical or biological properties compared to 2-aminoimidazolones shown in Figure 1. In this report, we wish to demonstrate the synthesis of 2-arylimidazolone (vi) via chemoselective addition of carbon nucleophile on variously substituted carbodiimides prepared from natural L-amino acids by using our previous method for construction of 3,4-dihydroquinazoline scaffold. The complete synthetic route is shown in Scheme 1: Ester of amino acid (1) was treated with isocyanate/Et3N to give urea 2a-c in 54-82% yields. Since benzylisocyanate was commercially unavailable, compound 2d was prepared in 84% yield by treating amino acid (1) with benzylamine/ triphosgene/Pr2NEt (Table 1). 7 Compound 2a-d were dehydrated with PPh3·Br2/TEA to provide the desired carbodiimide 3a-d in 42-59% yields. Finally, reaction of carbodiimide 3a-d with Grignard reagent or piperidine resulted in the formation of the corresponding 2-phenylimidazolone 5a and 2-piperidinylimidazolones 5 (e, g, i, and k) via tandem chemoselective addition on carbodiimidecyclization. The results are summarized in Table 1 and 2. In the case of L-phenylalanine (R1 = benzyl), the reaction of