UBC Theses and Dissertations
Development of efficient methods incorporating fluorinated motifs in organic molecules Foth, Paul
Di- and trifluoromethoxyarenes are industrially relevant motifs found in medicinal compounds, agrochemicals, and materials. However, the number of different strategies available to access these di- and trifluoromethoxy arenes are currently limited. Chapter 2 describes the development of a new fluorodecarboxylation method utilizing xenon difluoride for the synthesis of difluoromethoxyarenes. The reaction occurs rapidly and efficiently with facile purification, affording the desired difluoromethoxyarenes in 34–72% yields. Sulfuryl fluoride is an industrially produced insecticidal fumigant that has been utilized in synthetic chemistry primarily for the synthesis of aryl fluorosulfates. Chapter 3 details a new strategy using sulfuryl fluoride with 1,1-dihydrofluoroalcohols to synthesize 1,1-dihydrofluoroalkylamines. The reaction proceeds through a 1,1-dihydrofluoroalkyl fluorosulfate intermediate, which was demonstrated to be an effective alkylating agent for amines in contrast to previous reports. The method involves a one-pot, single step reaction and was applied to various 1,1-dihydrofluoroalcohols to access a variety of functionalized amines in 42–80% yields. 1,1-Dihydrofluoroalkyl sulfides are commonly synthesized via alkylation of thiols. These methods may require long reaction times or suffer poor selectivity for thiols in the presence of other nucleophiles. Chapter 4 describes the development of a new one-pot thiol 1,1-dihydrofluoroalkylation method using a new class of thiol 1,1-dihydrofluoroalkylating reagents. Bis(trifluoroethyl) sulfate was demonstrated to have excellent reactivity with thiols forming trifluoroethyl sulfides in 58–83% yields, even in the presence of competing amine, hydroxyl, and carboxylic acid functional groups. Additional 1,1-dihydrofluoroalcohols were similarly applied to access longer chain 1,1-dihydrofluoroalkyl sulfides in 70–90% yields. The utilization of sulfuryl fluoride to mediate one-pot transformations from carboxylic acids has been less explored compared to alcohols. Sulfuryl fluoride-mediated carboxylic acid activation has been previously utilized to access acyl fluorides over twelve hours. The long reaction time makes this method unsuitable for further one-pot nucleophilic acyl substitution reactions. Chapter 5 describes an accelerated synthesis of acyl fluorides from carboxylic acids using sulfuryl fluoride and tetrabutylammonium halide salts. Mechanistic investigations revealed that the accelerated reaction predominantly occurs through an acid anhydride intermediate. Acyl fluorides were afforded in 30–80% yields and subsequently utilized in the synthesis of esters, amides, and thioesters in 72–96% yields.
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