O-Alkylation of 3-hydroxyisoxazoles predominates under Mitsunobu conditions

Article abstract of DOI:10.1016/j.tetlet.2014.01.065

Regiochemical control in the functionalization of ambident nucleophiles is of particular interest in organic chemistry. Herein, we demonstrate that O-alkylation of ambident 3-hydroxyisoxazoles, which are heterocyclic bioisosteres of carboxylic acids, predominates under Mitsunobu conditions. In several cases, excellent O-regioselectivity (≥95%) was observed. It is noteworthy that reactions were complete within 15 min at room temperature. Furthermore, the conditions are compatible with a range of alcohols that cover all of the typical protecting groups for the 3-hydroxyisoxazole motif, providing milder, simpler and less hazardous protocols to those commonly followed in the literature.