Fluorinated pyrimidines. Part 4. Synthesis, properties and stereochemical conversion of the cis and trans isomers of 6-alkoxy-5-fluoro-5,6-dihydrouracils

Abstract

The reaction of 6-acetoxy-5-fluoro-5,6-dihydrouracil with ROH (R = Me, Et, Pr, Prⁱ, Bu, Bu^t) under acidic conditions has been investigated using ¹⁸F as a tracer. The quantitative replacement of the OAC-group proceeded predominantly with cisoid(gauche) stereochemistry, but upon prolonged heating the amount of the trans compound increased. This isomerization did not originate from epimerization at C⁵. The trans compounds—apart from being more stable towards substitution and elimination than the corresponding cis compounds—gave invariably substitution products with inversion of configuration, while the cis compounds mainly retained their configuration. Within the concept of the unifying ion-pair mechanism it is proposed that the trans compound reacts via an intimate protonated intermediate and the cis compound via a solvent-separated protonated intermediate. As a result, it was not the gauche attraction between the fluorine atom and the incoming nucleophile, but the poor π-donor ability of the C–F bond that was the determining factor in the cisoid stereochemistry of 5-fluoro-5,6-dihydrouracil adducts.