Photocatalytic Methods for Amine and Azacycle Synthesis

Abstract

Primary amines are among the most utilised functional group in organic chemistry, and their reactivity is intimately associated with the nucleophilic and basic character of their non-bonded electron pair. Almost all the known reactions of this critical compound class are predicated on this innate reactivity, with amide bond formation and nucleophilic aromatic substitution (SNAr) – which also happen to be the two most frequent reactions deployed in the pharmaceutical industry – being a case in point. For these reasons, temporary N-masking strategies are necessitated when the amino function is not the desired locus of reactivity, and this tends to markedly erode synthetic efficiency. The addition or excision of nitrogen protecting groups is the third most frequent transformation in drug discovery. In this thesis, a newly emerging strategy for alkylamine synthesis is explored that will enable the catalytic formation of carbon-carbon (C–C) bonds adjacent (α-) to the nitrogen atom of primary amines, without the need for any N-protecting or directing groups. Building on previous work from the Cresswell lab, visible light photoredox catalysis is used in combination with hydrogen atom transfer (HAT) co-catalysis to generate α-amino radicals from unprotected primary amines. These reactive intermediates are then trapped with various radical acceptors (radicophiles) to forge the new C–C bond, and this strategy is also effective for the synthesis of notoriously challenging α-tertiary amine products.Chapter 1 introduces the concepts of photoredox and HAT catalysis, and then summarises the relevant prior art for alkylamine synthesis by C–C bond formation.Chapter 2 describes a photocatalytic hydroaminoalkylation of primary amines, using styrenes as radicophiles. Applications to synthesis of lead-like N-heterocycles (tetrahydroquinolines) and a known pharmaceutical (Fingolimod) are also delineated.Chapter 3 details a new synthesis of 1,3-amino alcohols directly from primary amines, using a vinylboronic ester as a radicophile and hydroxyethyl equivalent.Chapter 4 outlines a new synthesis of azetidines directly from primary amines, by telescoping a photocatalytic C–C bond formation with a nitrenoid insertion into a C–B bond.

Date of Award	22 Jan 2025
Original language	English
Awarding Institution	University of Bath
Sponsors	AstraZeneca, Cambridge
Supervisor	Alex Cresswell (Supervisor), Steven Bull (Supervisor) & Gail Wrigley (Supervisor)