Radical methods for the synthesis of fluoroalkanes and fluoromethyl aryl ethers and copper-catalyzed three-component carboetherification of alkenes

Fluorinated molecules have become popular compounds among pharmaceuticals. The introduction of fluorine atoms on bioactive compounds has indeed the potential to improve their biophysical properties. Given the utility of fluorinated substituents on pharmaceuticals, fluorine chemistry has become an area of intensive research. Despite the progress made in selective fluorination, however, radical fluorination has been limited notably due to the paucity of atomic fluorine sources. In this thesis, the uncovering of new atomic fluorine sources and the development of new radical fluorination methods will be described. Chapter 1 presents the importance of fluorinated molecules and the currently available fluorinating agents. A discussion on radical fluorination is presented that includes the most recent advances in the field. In Chapter 2, the exploratory work on the ability of electrophilic N—F fluorinating agents to transfer fluorine to alkyl radicals is detailed. Peresters were chosen as radical precursors and reacted with traditionally electrophilic fluorine sources, NFSI and Selectfluor®. Under those conditions, various fluoroalkanes could be synthesized in good yields. A radical fluorination method subsequently developed using Selectfluor® is described in Chapter 3. The ability of phenoxyacetic acid derivatives to undergo fluorodecarboxylation under UV-light excitation using Selectfluor® was demonstrated. The methodology was successfully applied to the synthesis of mono- and difluoromethyl aryl ethers in 40 to 86% yields. Chapter 4 details the application of the photofluorodecarboxylation to the synthesis of trifluoromethyl aryl ethers. It was found that the wavelength required for the substrate’s excitation led to the decomposition of the desired products. A method using benzophenone as a photosentizer was developed allowing the use of another wavelength to promote the reaction, which proved to be substrate dependent. The use of a faster fluorine transfer agent, XeF2, allowed the synthesis of trifluoromethoxy arenes in good yields. A copper catalyzed difunctionalization of alkenes, developed in collaboration with Prof. Jieping Zhu, is presented in Chapter 5. This reaction allows the direct introduction of alkyl nitriles via C—H activation. A C—O bond and a C—C bond were created in a single step. A wide range of α substituted styrenes were difunctionalized in yields up to 82%.Science, Faculty ofChemistry, Department ofGraduat

Copper-Catalyzed Formal [2+2+1] Heteroannulation of Alkenes, Alkylnitriles, and Water: Method Development and Application to a Total Synthesis of (±)-Sacidumlignan D

A copper-catalyzed three-component reaction of alkenes, alkylnitriles, and water affords gamma-butyrolactones in good yields. The domino process involves an unprecedented hydroxy-cyanoalkylation of alkenes and subsequent lactonization with the creation of three chemical bonds and a quaternary carbon center. The synthetic potential of this novel [2+2+1] heteroannulation reaction was illustrated by a concise total synthesis of ()-sacidumlignan D

Copper-Catalyzed Intermolecular Carboetherification of Unactivated Alkenes by Alkyl Nitriles and Alcohols

A three-component carboetherification of unactivated alkenes has been developed allowing the rapid building of complexity from simple starting materials. A wide range of a-substituted styrenes underwent smooth reactions with unactivated alkyl nitriles and alcohols to afford g-alkoxy alkyl nitriles with concomitant generation of a quaternary carbon center. A radical clock experiment provided clear-cut evidence that the reaction proceeds through a tertiary alkyl radical intermediate

Fluorine Transfer to Alkyl Radicals

The development of new synthetic technologies for the selective fluorination of organic compounds has increased with the escalating importance of fluorine-containing pharmaceuticals. Traditional methods potentially applicable to drug synthesis rely on the use of ionic forms of fluorine (F^– or F⁺). Radical methods, while potentially attractive as a complementary approach, are hindered by a paucity of safe sources of atomic fluorine (F^•). A new approach to alkyl fluorination has been developed that utilizes the reagent <i>N</i>-fluorobenzenesulfonimide as a fluorine transfer agent to alkyl radicals. This approach is successful for a broad range of alkyl radicals, including primary, secondary, tertiary, benzylic, and heteroatom-stabilized radicals. Furthermore, calculations reveal that fluorine-containing ionic reagents are likely candidates for further expansion of this approach to polar reaction media. The use of these reagents in alkyl radical fluorination has the potential to enable powerful new transformations that otherwise would take multiple synthetic steps