Modular Methods for the Synthesis of α-Tertiary and α-Branched Alkylamines via Visible-Light-Mediated Radical Generation

Abstract

The efficient assembly of complex molecules from cheap and abundant feedstock materials is a central goal of organic synthesis. Alkylamines are interesting synthetic targets because they occupy a privileged position in drug discovery yet are often highly challenging to synthesise. Complex alkylamines commonly feature branching at the α-position, which can further complicate their synthesis. This thesis describes two methods for the preparation of alkylamines displaying either one (α-branched amines) or two (α-tertiary amines) α-branching substituents. In the first method, visible-light-mediated photoredox catalysis orchestrates the formation of α-tertiary amines from alkyl primary amines, alkyl ketones, and alkene acceptors. Over 50 new α-tertiary alkylamines are reported, displaying a range of structural and functional diversity in all three components. The new method enabled a single-step synthesis of the multiple sclerosis drug fingolimod (Gilenya), and provided access to a range of unique spirocyclic tetrahydronaphthyridine and tetrahydroquinoline scaffolds. Mechanistic studies inform the proposal of a redox-neutral catalytic cycle involving generation of a key α-amino radical. In the second method, α-branched amines are prepared from alkyl primary amines, alkyl aldehydes and alkyl iodides in an advancement of the carbonyl alkylative amination chemistry previously reported by the Gaunt group. Carbon-carbon bond formation takes place upon addition of an alkyl radical to an alkyl imine. Over 50 new a-branched alkylamines are reported, including the use of alkyl iodides bearing a pendent electrophile to enable annulation to form α-branched heterocycles in a telescoped two-step procedure. Preliminary results regarding a selective alkylation reaction at primary amines in the presence of cyclic secondary amines are also reported.