Synthesis of Fluorinated Heterocycles via Prins Cyclization in Ionic Liquids

Significance

Described is the synthesis of fluorinated tetrahydropyrans, thiacyclohexanes and piperidines via Prins cyclization using ionic liquid˙HF salts as the solvent and fluoride source. Several different ionic liquid˙HF salts were screened, with Et₄NF˙5HF found to be the best protic acid catalyst. Prins cyclization of both aliphatic and aromatic aldehydes 1 with homoallylic alcohols 2 rapidly gave cis-tetrahydropyrans 3 in excellent yields. Extension to the reaction of 1 with homoallylic thiol 4 and amine 6 to give thiacyclohexanes 5 and piperidines 7, respectively, was achieved although the stereoselectivity is slightly reduced in these cases. The reusability of the ionic liquid was demonstrated without loss of product yield for up to five runs.

Comment

Organofluorine compounds are of increasing utility in medicinal, agrochemical and materials chemistry (see Book below). The Prins cyclization is a powerful method for the construction of halogenated and hydroxylated tetrahydropy­rans; however, few satisfactory methods are known for the preparation of fluorine-containing tetrahydropyrans. The current method provides a rapid, efficient and environmentally benign method for the synthesis of saturated 4-fluoro six-membered heterocycles. The reaction scope was adequately studied with respect to both the aldehyde and homoallylic alcohol.

Book

Science of Synthesis, Vol. 34; Georg ­Thieme Verlag: Stuttgart, 2006.