New photochemical methods for the synthesis of aromatics and azoles

Abstract

The first part of this thesis introduces two novel photochemical strategies utilizing readily available nitroarenes for singlet nitrene generation and HAT chemistry in order to synthesize ortho-dianilines and anilines. The first chapter will present a one-pot approach for directly converting nitroarenes and complex amines into ortho-phenylenediamines. This method offers a new retrosynthetic perspective, where the amine coupling partner seemingly “replaces” the nitro group, which undergoes a formal 1,2-shift to the ortho position, forming the desired product in a streamlined manner. Mechanistically, the reaction proceeds via nitrobenzene-derived singlet nitrenes, followed by a sequence of N-insertion, electrocyclic ring expansion, amine addition, and electrocyclic ring contraction, ultimately yielding ortho-phenylenediamines. The second chapter explores the reduction of nitroarenes to anilines through a visible-lightdriven process involving an amine-borane complex and hypoboric acid. Preliminary mechanistic investigations suggest that boryl radicals are generated via a HAT event from the photoexcited nitroarene. Additionally, a parallel thermal pathway contributes to the reaction’s high efficiency, highlighting the interplay between photochemical and thermal processes. Electron-rich heteroaromatic compounds are privileged motifs in drug discovery and agrochemistry. However, their synthesis often requires tailored strategies, and in some cases, the lack of robust synthetic methods can hinder or even prevent the preparation of specific derivatives for further study. The second part of this thesis introduces a novel approach to azole synthesis, leveraging UV light to selectively and predictably modify their core structures. The third chapter introduces a novel strategy for selectively modifying thiazole and isothiazole cores through photochemical irradiation. Upon excitation to their π,π* singlet states, these heterocycles undergo a sequence of structural rearrangements, ultimately leading to a controlled reorganization of the ring system and its substituents. This approach allows for the systematic transformation of an initial heteroaromatic scaffold into a range of related molecules under mild conditions that accommodate diverse functional groups. Preliminary results also suggest that this method could be extended to other azole frameworks, such as benzo[d]isothiazole, indazole, pyrazole, and isoxazole. The final chapter presents a photochemical approach for directly converting isoxazoles into various electron-rich heterocycles. By harnessing their singlet excited state, this method enables two distinct pathways: selective transformation into oxazoles or fragmentation into α- ketonitriles, which can then serve as intermediates for the synthesis of pyrazoles, isothiazoles, and pyrroles. This strategy provides a powerful tool for modifying heterocyclic scaffolds at a late-stage, facilitating the rapid construction of diverse chemical libraries.

Date of Award	12 May 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Jordi Bures (Supervisor), Guillaume De Bo (Supervisor) & Daniele Leonori (Supervisor)