Photochemical α-C−H Functionalisation of Primary Amines

Abstract

Amines are among the most valuable functional groups in organic chemistry, owing both to their widespread pharmacological relevance in medicinal compounds and to their versatility as synthetic intermediates. Traditionally, amine reactivity is dominated by nucleophilicity at the nitrogen atom, with divergent reactivity at the C−H bond α- to nitrogen remaining significantly underexplored, despite offering complementary and potentially powerful synthetic opportunities. This mode of reactivity is particularly underrepresented on primary amines, whereby most successes have necessitated the protection of the amine nitrogen to facilitate reactivity at the desired α-C−H position. Our lab has recently developed a catalytic way to achieve α-C−H functionalisation on unactivated primary amines without the need for N-protection. To achieve this, visible light photoredox catalysis is used in combination with hydrogen atom transfer co-catalysis, generating α-amino radicals as synthetic intermediates. These species can then be trapped with radicophiles, affording C−C bonded products.

Chapter 1 outlines the key literature for carrying out α-C−H functionalisation of primary amines, covering processes which use N-protecting/directing groups alongside those which do not. The chapter also explains the prior work developed by Cresswell and co-workers.
Chapter 2 describes the attempted synthesis of 1,2-amino alcohols using aldehydes as radicophiles towards α-C−H functionalisation with primary amines. To prevent radical reversibility with the carbonyl group, N-masking groups (N-boryl, N-formyl, and carbamates) were explored.
Chapter 3 explores the synthesis of 1,3-amino alcohols from primary amines using vinyl siloxanes as radicophiles, utilising Fleming-Tamao oxidation of the γ-amino siloxane intermediate to access the corresponding 1,3-amino alcohol.
Chapter 4 explores the synthesis of azetidines from primary amines, using vinyl sulfonium salts as radicophiles. This chapters also demonstrates a kilogram scale-up campaign carried out by Pharmaron.
Chapter 5 explores the use of vinyl sulfones as radicophiles with primary amines, gaining access to γ-amino sulfones. These species were further functionalised, affording a cyclic sulfonamide (sultam), a cyclic sulfinamide, and a N-protected γ-amino sulfonyl fluoride.
Chapter 6 contains the experimental procedures and characterisation data relating to the work carried out in chapters 2-5.

Date of Award	24 Jun 2026
Original language	English
Awarding Institution	University of Bath
Supervisor	Alex Cresswell (Supervisor), Steven Bull (Supervisor) & Martin Ernst (Advisor)