One-step synthesis of 5-acylisothiazoles from furans

Premixed ethyl carbamate, thionyl chloride and pyridine (which generate thi azyl chloride, N=SCl) in boiling benzene or toluene convert 2,5- and 2,3,5- substituted furans into 5- acylisothiazoles regiospecifically. The reactio ns are much faster and generally higher yielding in boiling chlorobenzene w ith more thionyl chloride and with pyridine or isoquinoline as base. Under the more vigorous conditions, even fully substituted 3-bromofurans give iso thiazoles, with the displacement of bromine. Deactivated furans, with elect ron-withdrawing groups such as ester, cyano, benzoyl and phenylsulfonyl in the alpha -position, react under the more vigorous conditions to give 5- ac ylisothiazoles with the electronegative group in the 3-position. The 'activ ated' 2-methyl-5-phenyl- and 5-phenyl-2-phenylthio-furans react analogously , with the more electron-releasing group becoming part of the 5- acyl subst ituent, exclusively or predominantly. These results are explained by initia l electrophilic attack of the furan ring to give beta -thiazyl derivative w hich spontaneously ring-opens and closes to the isothiazole. The X-ray stru ctures of ve of the differently substituted isothiazole compounds are repor ted. All have very similar patterns of bonding within their isothiazole rin gs that appear to be independent of the electron-withdrawing or -donating n ature of the substituents. Three of the compounds (8a, 8g and 13) have loos ely linked chain structures in the solid state, adjacent molecules being co nnected by combinations of hydrogen bonding and pi-pi stacking interactions .