title: Synthesis of 3-(1-Methyl-1H-imidazol-2-ylthio)propanoic Acid and (E)-3-(1-Methyl-1H-imidazol-2-ylthio)acrylic Acid.
abstract: The syntheses of 3-(1-methyl-1H-imidazol-2-ylthio)acrylic acid and 3-(1-methyl-1H-imidazol-2-ylthio)propanoic acid, mitochondria-targeted prodrugs of the antioxidant methimazole, are described. The method of Fan et al. (Fan et al.,Synthesis2006, 2286) for the reaction of phenols with propiolic acid and propiolate esters was modified to synthesize (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylic acid. The intermediatetert-butyl (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylate was prepared by the reaction oftert-butyl propiolate with methimazole; the use oftert-butyl propiolate rather than methyl propiolate gavetert-butyl (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylate as the predominant isomer. Acid hydrolysis of the intermediate ester afforded the target compound. 3-(1-Methyl-1H-imidazol-2-ylthio)propanoic acid was synthesized from 3-bromopropanoic acid and methimazole under conditions that gave preferential substitution on sulfur and minimized substitution on nitrogen.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hattan
authors.affiliation: Mitochondrial Research and Innovation Group, Department of Anesthesiology, and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Jalil
authors.initials: J
authors.lastname: Shojaie
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721.
authors.forename: Serrine S
authors.initials: SS
authors.lastname: Lau
authors.affiliation: Mitochondrial Research and Innovation Group, Department of Anesthesiology, and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
keywords: alkyne activation; antioxidants; methimazole; thiols; β-oxidation