Syntheses and pKa determination of 1-(o-hydroxyphenyl)imidazole carboxylic esters

All three isomers of 1-(o-hydroxyphenyl)imidazole carboxylic esters (1-3) have been synthesized regioselectively via their methyl ether precursors. Methyl 1-(o-methoxyphenyl)imidazole-2-carboxylate (6) and the corresponding 1,4-isomer (11) were synthesized via Cu-catalyzed coupling of 2-iodoanisole with imidazole followed by methoxycarbonylation, and by direct coupling of 2-iodoanisole with methyl imidazole-4-carboxylate (7), respectively. The 1,5-isomer (15) was prepared by annulation of an N-aryl glycine ester derivative (13). The boron tribromide mediated cleavage of methyl ethers gave the hydroxyphenyl compounds (1-3) in good to excellent yields. These compounds can serve as building blocks for synthesizing a new generation of active-site model compounds of cytochrome c oxidase (CcO). The pK(a) values have been determined by spectrophotometric measurements in order to provide a basis for the understanding of the proton transfer processes in CcO.