Synthesis of Derivatives of Hexafluoroisopropanol

Abstract

Fluorinated organic molecules have significant potential in medicinal chemistry and drug discovery. Consequently, 20–25% of the FDA approved drugs contain at least one fluorine atom. Functional groups displaying high levels of fluorination are attracting new interest to expand the chemical space for drug development. A hexafluoroisopropanol (HFIP) group is one of these groups which combines high levels of fluorination with an adjacent alcohol. This functionality displays a unique hydrogen bond donor without any nucleophilicity. Recent studies have shown that the HFIP can be employed as a building block for the synthesis of drug-like molecules, and its incorporation into small molecules can significantly improve their biological activity. Unfortunately, few methods to install a HFIP group exist in the literature and the scope of starting materials that participate in these reactions are not well explored. We hypothesize that the Colby trifluoromethylation reagent, which contains hexafluoroacetone hydrate, can be used in the synthesis of derivatives of HFIP from anilines and other substrates. Using this reagent, we optimized a procedure through variations in time and temperature and we examined the role of acid catalysts. The optimal conditions were identified using 19F-NMR for the determination of yield. Currently, we are expanding the scope of the reaction using different substrates and conditions. Our goal is a high yield procedure with mild conditions. We believe that a method to produce derivatives of HFIP will be significant in the drug design and development.