N-Heterocyclic carbene acyl anion organocatalysis by ball-milling

The ability to conduct N‐heterocyclic carbene‐catalysed acyl anion chemistry under ball‐milling conditions is reported for the first time. This process has been exemplified through applications to intermolecular‐benzoin, intramolecular‐benzoin, intermolecular‐Stetter and intramolecular‐Stetter reactions including asymmetric examples and demonstrates that this mode of mechanistically complex organocatalytic reaction can operate under solvent‐minimised conditions

Electrochemical alkene azidocyanation via 1,4-nitrile migration

An electrochemical method for the azidocyanation of alkenes via 1,4-nitrile migration has been developed. This organic oxidant free method is applicable across various alkene containing cyanohydrins, and provides access to a broad range of synthetically useful 1,2-azidonitriles (28 examples). This methodology was extended to an electrochemical alkene sulfonylcyanation procedure, as well as to access a trifunctionalized hexanenitrile from a malononitrile starting material. The orthogonal derivatization of the products was also demonstrated through chemoselective transformations

Manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols via alkoxy radicals

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on a gram scale

Ball-milling-enabled reactivity of manganese metal

Efforts to generate organomanganese reagents under ball-milling conditions have led to the serendipitous discovery that manganese metal can mediate the reductive dimerization of arylidene malonates. The newly uncovered process has been optimized and its mechanism explored using CV measurements, radical trapping experiments, EPR spectroscopy, and solution control reactions. This unique reactivity can also be translated to solution whereupon pre-milling of the manganese is required

Electrochemical deconstructive functionalization of cycloalkanols via alkoxy radicals enabled by proton-coupled Electron transfer

Herein, we report a new electrochemical method for alkoxy radical generation from alcohols using a proton-coupled electron transfer (PCET) approach, showcased via the deconstructive functionalization of cycloalkanols. The electrochemical method is applicable across a diverse array of substituted cycloalkanols, accessing a broad range of synthetically useful distally functionalized ketones. The orthogonal derivatization of the products has been demonstrated through chemoselective transformations, and the electrochemical process has been performed on a gram scale in continuous single-pass flow

Investigations into the development of new methodologies for organic electrochemistry

This thesis describes investigations into the development of new electrochemical methodologies applicable to organic synthesis. Initial investigations were focused on the development of new strategies for the generation and utilisation of alkoxy radicals under electrochemical conditions. To this end, a new procedure for an electrochemical manganese-catalysed deconstructive chlorination of cycloalkanols was developed. In this study, tertiary cyclopropanols and cyclobutanols were conveniently converted into synthetically useful distally chlorinated ketones via alkoxy radical intermediates. This methodology utilises an inexpensive manganese (II) pre-catalyst to facilitate the synthesis of a diverse range of β- and γ-chloroketones (40 examples, 30-90% yield). Facile scale-up was also performed by employing a recirculating flow-electrochemistry system and mechanistic investigations, including the use of cyclic voltammetry, allowed the proposal of alkoxy radical intermediates. Further work on the electrochemical generation of alkoxy radicals was then performed to overcome the limitations associated with the manganese-catalysed method. This work centred around the use of cerium (III) or (IV) salts to generate alkoxy radicals under electrochemical conditions. Following these unsuccessful investigations, the development of a photoelectrochemical system for the cerium-mediated generation of alkoxy radicals was subsequently explored. Chapter 4 of this thesis then describes investigations into an electrochemical alkene hetero-difunctionalisation procedure that proceeds via a 1,4-nitrile migration. In this study, cyanohydrin substrates bearing a distal alkene were converted into synthetically useful 1,2-azidonitriles using a manganese (II) salt as an azide transfer reagent (28 examples, 27-75% yield). This methodology was then extended to perform electrochemical alkene sulfonylcyanation and trifluoromethylcyanation, as well as to access a trifunctionalised hexanenitrile from a functionalised malononitrile starting material. The utility of the products formed was demonstrated through orthogonal derivatisation, and mechanistic investigations, including cyclic voltammetry studies and a radical clock experiment, allowed the proposal of radical intermediates within the reaction mechanism

Ball Milling Enabled Reactivity of Manganese Metal

Efforts to generate organomanganese reagents under ball milling conditions have led to the serendipitous discovery that manganese metal can mediate the reductive dimerization of arylidene malonates. The newly uncovered process has been optimized and its mechanism explored using CV measurements, radical trapping experiments, EPR spectroscopy and solution control reactions. This unique reactivity can also be translated to solution where upon pre-milling of the manganese is required

Manganese-Catalyzed Electrochemical Deconstructive Chlorination of Cycloalkanols via Alkoxy Radicals

A manganese-catalyzed electrochemical deconstructive chlorination of cycloalkanols has been developed. This electrochemical method provides access to alkoxy radicals from alcohols and exhibits a broad substrate scope, with various cyclopropanols and cyclobutanols converted into synthetically useful β- and γ-chlorinated ketones (40 examples). Furthermore, the combination of recirculating flow electrochemistry and continuous inline purification was employed to access products on gram scale. </div