Controlling the regioselectivity of the bromolactonization reaction in HFIP

Abstract

The halolactonization reaction provides rapid access to densely functionalized lactones from unsaturated carboxylic acids. The endo/exo regioselectivity of this cyclization reaction is primarily determined by the electronic stabilization of alkene substituents, thus making it inherently dependent on substrate structures. Therefore this method often affords one type of halolactone regioisomer only. Herein, we introduce a simple and efficient method for regioselectivity-switchable bromolactonization reactions mediated by HFIP solvent. Two sets of reaction conditions were developed, each forming endo-products or exo-products in excellent regioselectivity. A combination of computational and experimental mechanistic studies not only confirmed the crucial role of HFIP, but also revealed the formation of endo-products under kinetic control and exo-products under thermodynamic control. This study paves the way for future work on the use of perfluorinated solvents to dictate reaction outcomes in organic synthesis.