Epoxide Opening with Tetrabutylammonium Fluoride (TBAF)

Abstract

Positron emission tomography (PET) has been used to assess the fundamental and neurochemical parameters in normal and diseased human organisms. Measuring these parameters with PET requires the preparation of specific molecular imaging probes labeled with positron-emitting radioisotopes. Labeling pharmaceuticals with [F]fluorine often enables the fluorine-substituted analogue to be used to trace biochemical processes while maintaining favorable interaction with the target. Thus, a rapid and effective method for the introduction of F is a great concern in organofluorine and radiopharmaceutical chemistry. The typical method for introduction of a fluorine atom in an aliphatic molecule is the nucleophilic substitution of the corresponding sulfonates or halides by a fluoride ion. For example, the reaction of 2-(3-methanesulfonyloxypropoxy)naphthalene with CsF in t-BuOH gave 2-(3-fluoropropoxy)naphthalene in 92% yield along with the corresponding ether. Epoxide opening with a fluoride ion has been widely used in the preparation of fluorohydrins, which were often found in a certain bioactive molecules such as steroids, amino acids, carbohydrates, and prostaglandins. Anhydrous hydrogen fluoride is a good reagent for cleavage of the epoxide ring, but it is not easy to handle due to its toxicity and corrosiveness. To avoid this problem, some reagents have been developed; HF-amine complex, potassium hydrogen difluoride, silicon tetrafluoride, tetrabutylammonium dihydrogen trifluoride, and so on. Although these reagents gave successful results to some extent, most cases require heating at high temperature for a long period. In consequences, byproducts were often resulted from elimination, rearrangements or polymerization. Metal fluoride[F] or tetrabutylammonium fluoride[F] (TBAF) is a good source of the fluorinating agent to prepare radiopharmaceuticals containing F, but they were rarely used in the epoxide ring opening reaction. In this report, we examined epoxide opening reactions with metal fluoride or TBAF for introducing [F]fluorine to fluorohydrins.