Studies on the Photocatalytic α-C–H Alkylation of Unprotected Primary Amines

Abstract

Saturated N-heterocycles are valuable scaffolds for drug discovery and are highly prevalent in natural bioactive molecules. Methods for their synthesis have developed significantly over the past 20 years but despite this, modular routes towards complex pyrrolidines and piperidines remain limited. Hence, this work focuses on the development of modular and scalable routes to complex (e.g., spirocyclic) γ- and δ-lactams as intermediates towards pyrrolidines and piperidines.

Chapter 1 acts as an introduction to current synthetic strategies for saturated N-heterocycles with a focus on recent (2020–present) literature in this area.

Chapter 2 outlines a second generation synthesis of γ-lactams from unprotected primary amines, building on previous work from our laboratory. Reactions are performed in automation using continuous flow chemistry to highlight the relevance of this method to library synthesis. An alternative route to γ-lactams is also reported, via γ-amino nitriles. Intermediate γ-amino nitriles were formed in moderate-to-good yield [22–65% (after tosylation)] by addition of α-amino radicals to acrylonitrile. Hydrolytic cyclisation of these intermediates afforded simple γ-lactams in good yield (up to 86%, over two steps) and this strategy improved the yields of several α-monosubstituted lactams (vs the previous route using methyl acrylate).

Chapter 3 details development of an automated δ-lactam synthesis to provide a modular route to piperidines, the second most popular N-heterocycle in small molecule drugs. Photocatalytic annulation of unprotected primary amines with a substituted, low cost acrylate afforded α-disubstituted δ-lactams (including α-spirocyclic examples) in excellent yield (54–94%). α-Monosubstituted δ-lactams proved more challenging but most were produced in good yield (20–61%). Use of continuous flow chemistry meant that minimal re-optimisation was required upon scaling the reaction to 10 g, providing a highly time- and cost-effective synthesis of a complex, spirocyclic scaffold (STY = 0.6 g h-1 mL-1).

Chapter 4 describes mechanistic observations of the photocatalytic hydroaminoalkylation of styrenes with unprotected amines. A Stern-Volmer luminescence quenching study confirmed quenching of excited state 3DPA2FBN by N3- (KSV = 1.19 × 103 M-1). Kinetic analysis (VTNA) was consistent with the reaction being zero order in the amine and both catalysts, suggesting photon-limited conditions. However, observation of first order kinetics in the styrene conflicted with this, suggesting a transition to a nonphoton-limited regime. Further investigation revealed three reaction phases: an initial induction period, followed by a photon-limited phase (k = 14.4 mmol dm-3 min-1), followed by a non-photon-limited phase.

Chapter 5 contains the experimental procedures, characterisation data, and other results relating to the work in chapters 2–4.

Date of Award	26 Mar 2025
Original language	English
Awarding Institution	University of Bath
Supervisor	Alex Cresswell (Supervisor), James Taylor (Supervisor) & Maria Ciaccia (Supervisor)