UBC Theses and Dissertations

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UBC Theses and Dissertations

Development of efficient methods for the syntheses of fluorinated motifs using fluorinated gases Lee, Chia Wei


Sulfonyl fluorides, alkyl fluorides and acyl fluorides are common functional groups found in numerous industrial products, including in pharmaceuticals, agrochemicals, and functionalized materials. In spite of numerous methods developed, there are still many limitations in the existing protocols to access these fluorinated motifs. This thesis describes my contribution to the development of new synthetic methods to access sulfonyl fluorides, alkyl fluorides, and acyl fluorides using two fluorinated gases, sulfuryl fluoride and thionyl fluoride. Chapter 1 gives a broad introduction to applications of fluorochemicals in pharmaceutical, polymer, and agrochemical industries, which contribute significantly to market share and revenue. Syntheses of fluorochemicals are of great interest in synthetic chemistry using various fluorinating reagents. This chapter details the development and transformations of two gaseous fluorinating reagents, sulfuryl fluoride and thionyl fluoride. Chapter 2 details the development of a novel fluorosulfurylation of Grignard reagents using sulfuryl fluoride. The reaction converts a wide range of alkyl, aryl, and heteroaryl Grignard reagents into the corresponding sulfonyl fluorides in 18-78% yields. A unique advantage of this method over previously reported fluorosulfurylation reactions is that the generated sulfonyl fluorides can be used to access unsymmetrical diaryl sulfones, sulfonate esters, and sulfonamides in a one-pot process. The development of an efficient deoxyfluorination of alcohols using sulfuryl fluoride to synthesize alkyl fluorides is reported in chapter 3. The broad scope including primary and secondary aliphatic alcohols in 46-92% yields demonstrated a good functional group tolerance and net inversion of configuration. A gram-scale synthesis proved the potential synthetic relevance of this methodology. Chapter 4 describes the development of ex situ generation of thionyl fluoride and subsequent demonstration of its use to access amino acid fluorides in 86-98% yields under mild conditions and short reaction time. The method is applicable for sequential reaction, whereby the generated amino acid fluorides can be converted to the corresponding dipeptides in a one-pot, column-free process with retention of optical purity. The broad scope allows for natural and unnatural amino acid substrates with a wide array of protecting groups. The new approach was applied to the sequential liquid phase peptide synthesis and solid phase peptide synthesis.

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