Studies on one-pot sulfuryl fluoride-mediated transformations of aliphatic alcohols

This thesis describes my contributions to the development of new synthetic methods that employ fluorinated reagents and/or access fluorinated motifs. In Chapter 2, investigations on di- and trifluoromethoxylation of heterocyclic and bioactive molecules is presented. α,α-Difluoroaryloxyacetic acids were employed as precursors to two pharmaceutically relevant motifs, tri- and difluoromethoxyarenes. The syntheses of the former were found to be challenging due to poor solubility or degradation of the starting material. The latter, on the other hand, were successfully accessed through a thermal acid-mediated protodecarboxylation. Chapter 3 details the development of a novel method to access N-trifluoroethylamines. Sulfuryl fluoride, a commodity chemical produced industrially on a large scale, was used to activate trifluoroethanol, and the resulting product, trifluoroethyl fluorosulfate, was found to trifluoroethylate amines. The initial studies focused on a two-step trifluoroethanol activation-substitution process. With the aid of kinetic data, we were later able to successfully combine two steps into an operationally simpler one-pot protocol. Using this one-pot approach we demonstrated trifluoroethylation of a range of primary and secondary amines in moderate to good yields (31-72%). Chapter 4 describes the development of a general one-pot method of SO2F2-mediated aliphatic alcohol substitution. During preliminary optimization studies, we found the choice of base to be an important factor. DBU proved to be uniquely effective, potentially due to its involvement in the activation of sulfuryl fluoride. The one-pot substitution was demonstrated for a range of alcohols with nitrogen-, sulfur-, and carbon-based nucleophiles (12-95% yields) under mild conditions in only 10 minutes. One of the reactions was also successfully performed on a gram-scale, and the product purification was achieved without chromatography. In Chapter 5, the development of a novel primary alcohol deoxygenation method is described. During preliminary investigations, we found that primary alcohols could be readily converted to the corresponding alkyl iodides through the one-pot activation with sulfuryl fluoride followed by nucleophilic substitution. The alkyl iodides could then be dehalogenated under radical conditions. Using this two-step process, we demonstrated deoxygenation of several primary alcohols in moderate to excellent yields (38-95%). Importantly, this approach tolerated several functional groups which are typically reduced by other common deoxygenation methods.

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