Chapter 3 - Thiophenes, hydrothiophenes, benzothiophenes, and related compounds

Abstract

This chapter reviews thiophenes and methods of their preparation. A useful method for the preparation of 2,3-disubstituted thiophenes is based on the nucleophilic ring opening of 2-ethoxycarbonylcyclopropyl-(triphenyl)phosphonium tetrafluoroborate with various alkali-metal thiocarboxylates in tetra hydro furan (THF). Initially this reaction leads to a stabilized phosphorane that undergoes a non-classical Wittig cyclization to produce the 2,3-disubstituted 4,5-dihydro-thiophene. The latter is then dehydrogenated with DDQ in dichloromethane either at room temperature or at reflux to give the corresponding thiophene. In addition, a simple synthesis of 2-substituted and 2,3-disubstituted alkyl and aryl thiophenes has been developed that commences with an aldol reaction between a chlorozinc ketone enolate and O-ethyl-[(2-oxoethyl)thio]thioformate. Exposure of the resulting aldol adduct to 1-methylpiperazine liberates the five-membered mixed thiohemiketal which can be readily dehydrated to the substituted thiophene with conc. HCl. A general synthesis of tetrasubstituted thiophenes involves the preparation of 3,4-dihydroxythiolanes from diketo sulfides by intramolecular reductive coupling with a low-valent titanium reagent at 0 oC or room temperature.