The Synthesis and α-Functionalisation of Amines via Visible Light Mediated Catalysis

Abstract

The ubiquity of amines in pharmaceutical, agrochemical and advanced materials has incentivised modern synthetic chemists to develop novel and innovative methods for their synthesis and functionalisation. Specifically, the direct alpha-C-H functionalisation of aliphatic amines represents one such transformation which demands further development and improvement of current methodology. Visible-light mediated catalysis has presented a powerful platform to facilitate this transformation, with several pathways established to achieve the alpha-functionalisation of amines.

This thesis is an exploration of the visible-light mediated functionalisation of aliphatic amines. Specifically, it explores the formal alpha-functionalisation of amines via the generation of alpha-amino radicals as key intermediates and investigates subsequent pathways of reactivity. The methodologies developed have been applied to the synthesis of biologically relevant amine scaffolds. Upon optimisation, continuous flow protocols were established to enhance the photochemical reaction conditions.

Chapter 1 summarises the protocols for the alpha-functionalisation of amines. A brief history of this transformation is explored, highlighting several methodologies and is accompanied by a critical evaluation of their benefits and limitations. The concept and principles of photoredox catalysis are introduced and notable examples examined within the context of photocatalytic protocols for amine alpha-functionalisation. Finally, flow chemistry is presented detailing its advantages with emphasis towards photoredox catalysis.

Chapter 2 establishes a visible-light mediated transfer hydrogenation of diarylmethimines. This process makes use of the single electron reduction of imines to engender alpha-amino radicals with triethylamine functioning as both a sacrificial reductant and hydrogen source. The developed conditions enabled the synthesis of a series of diarylmethamines to be synthesised with excellent chemoselectivity. A plausible mechanism was established, highlighting the dual role of triethylamine. Flow engineering enabled this procedure to be efficiently scaled to synthetically useful quantities with retention of the chemoselectivity established in batch.

Chapter 3 details the development of the decarboxylative alpha-alkylation of fused heterocyclic amines. This process engages fused heterocyclic amines and N-hydroxy phthalimide esters as radical surrogates to simultaneously establish both alpha-amino and alkyl radicals. Upon in situ generation of alpha-amino and alkyl radicals, radical-radical coupling produces the desired alpha-alkylated amine. The addition of co-reductant, diphenylamine is believed to facilitate a second mechanistic pathway that proceeds concurrently and improves the efficiency of this transformation. A flow protocol established more favourable reaction conditions, enabling conjugation of a variety of biologically active derivatives in typically good yields.

Chapter 4 introduces the concept of the tandem photocatalytic cycle revealing that in situ generation of a highly reducing iridium species establishes an effective pathway for single electron reduction of energy demanding substrates. This chapter further extends the knowledge of the tandem photoredox cycle, applying this mechanism towards the radical-radical coupling of alpha-amino and alkyl radicals. Accessing a highly reducing species enabled the single electron reduction of energy demanding alkyl halides; substrates previously difficult to access. This chapter further investigates the tandem photocatalytic cycle and establishes an alternative protocol for alpha-amino sp3 C-C bond formation.