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A new radical trifluoromethoxylation strategy and investigation on the fluorination of boronic acids using electrophilic N-F reagents

University of British Columbia

Fluorine-containing motifs are important components in pharmaceuticals and agrochemicals. Upon incorporation of fluorinated moieties, many small molecules show enhanced bioavailability, lipophilicity and metabolic stability. Despite their industrial importance, many fluorinated motifs remain a significant synthetic challenge. This thesis describes the investigation and development of new radical fluorination methods for the synthesis of two important, and synthetically challenging fluorinated motifs: trifluoromethoxyarenes and aryl fluorides. Chapter 1 provides a literature survey on the importance of fluorinated small molecules and outlines current methods to synthesize them. The chapter begins with a historic overview of fluorinated pharmaceuticals. Common fluorination reagents are then summarized, including anionic, cationic, and radical sources of fluorine. The chapter concludes with a brief survey of the application of ¹⁸F-fluorinated molecules in Positron Emission Tomography (PET). Chapter 2 outlines work towards the development of a radical fluorodecarboxylation methodology for the synthesis of trifluoromethoxy ethers. The chapter begins with a review of synthetic methodologies to access trifluoromethoxylated molecules that have been developed over the last few decades. Next, a novel methodology based on a radical fluorodecarboxylation method will be presented along with substrate scope studies. XeF₂ was used both to induce decarboxylation and as atomic fluorine source. The reaction afforded good yields for electron-rich substrates, whereas electron-deficient substrates and naphthol derivatives produced lower yields. Chapter 3 outlines work for the fluorination of aryl boronic acid and boronated derivatives using Selectfluor®. The chapter starts with a brief overview of known methodologies in fluorination of boronic acid derivatives. Studies towards synthesizing aryl fluorides from a number of boronic acid and boronate ester derivatives will then be described. Preliminary results of this transition metal-free method showed that the reaction is substrate dependent, and the general product yields were low.

Text

2016-01-05

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/56232

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/