Synthesis of 3-(1-methyl-1H-imidazol-2-ylthio)propanoic acid and (E)-3-(1-methyl-1H-imidazol-2-ylthio)acrylic acid

Christopher M. Hattan, Jalil Shojaie, Serrine S. Lau, M. W. Anders

Research output: Contribution to journalArticle

1 Scopus citations

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. (Synthesis 2006, 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 intermediate tert-butyl (E)-3-(1-methyl-1H-imidazol-2- ylthio)acrylate was prepared by the reaction of tert-butyl propiolate with methimazole; the use of tert-butyl propiolate rather than methyl propiolate gave tert-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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalSynthetic Communications
Volume43
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Alkyne activation
  • antioxidants
  • methimazole
  • thiols
  • β-oxidation

ASJC Scopus subject areas

  • Organic Chemistry

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