New Methods in Radical Chemistry: The Interplay of Halogen-Atom Transfer and Copper Catalysis

Abstract

Metal catalysed cross-coupling reactions have become the backbone of modern organic synthesis as they provide a straightforward and programmable approach to C-C and C-X (X = heteroatom) bond formation. While palladium-based systems have historically been the most prominently used catalysts, copper catalysis is now becoming one of the most common alternatives owing to its low cost, high sustainability and often orthogonal reactivity. This thesis focuses on the development of novel reactivities merging radical chemistry with copper-catalysis. At first, my PhD studies were focused on developing an Ullmann-Goldberg-type amination of unactivated alkyl iodides. This strategy was based on the activation of alkyl iodides by a-aminoalkyl radical-mediated halogen-atom transfer and the interplay of the corresponding radical with a copper catalytic-cycle to enable C(sp3)-N bond formation using several types of N-nucleophilic partners under mild and sustainable conditions. This process displayed a broad scope, allowing the late-stage modification of densely functionalised pharmaceuticals. Next, this reactivity blueprint was applied to the use of C-nucleophiles in order to assemble C(sp3)-C(sp2) bonds. The methodology that we developed enabled the coupling of alkyl iodides with pre-activated aryl, vinyl, benzylic, and allylic organoborons. While resembling the Nobel prize-winning Suzuki-Miyaura reaction in terms of retrosynthetic disconnection, our protocol operates under a mechanistically distinct fashion, and provides a convenient alternative for notoriously troublesome cross-couplings. The final part of my PhD studies was focused on the development of a new halogen-atom transfer reagent. It turned out that simple cyclohexadiene derivative, g-terpinene, can be used as the abstractor. The reaction is enabled by quantum mechanical tunnelling through a formal H atom intermediate. Dehalogenation of aryl and alkyl halides, including chlorides, was achieved under mild photoredox conditions. Furthermore, this approach was successfully applied to C-C bond formation via Giese reactivity.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jordi Bures (Supervisor) & Daniele Leonori (Supervisor)