Modular Approaches for the Synthesis of α-Azinyl Amines and Related Scaffolds

The work in this thesis comprises three projects all with a central focus on the synthesis of α-alkyl 2-azinyl amines and related scaffolds in a modular fashion. The first project describes the development of an operationally straightforward and general multicomponent carbonyl azinylative amination process. This protocol, which employs elemental indium as a reducing agent and a silyl triflate Lewis acid, facilitates access to a wide range of novel heterobenzylic amines from readily available aldehyde or ketone, amine and heteroaryl halide feedstocks. This work builds upon prior work carried out in the Gaunt group towards a general approach for complex amine synthesis and represents a significant and complementary advance and on our previously reported carbonyl alkylative amination platform. Here we also reveal the underexplored utility of a 2-azinyl anion equivalent that we believe manifests in the form of an organoindium species, identified through a series of mechanistic experiments. The reactivity of this putative intermediate is investigated through its reactions with other common electrophilic partners, enabling the efficient synthesis of functionalised tertiary alcohols, including an aza analogue of an antipsychotic drug haloperidol. To further demonstrate its synthetic utility, the carbonyl azinylative amination reaction was leveraged to enable the synthesis of nitrogen-rich and pharmaceutically-relevant α-azinyl piperidines. Proposed future work is also presented, including the realisation of a comprehensive platform for the assembly of heterocyclic scaffolds which contain the α-alkyl 2-azinyl amine motif, namely 7-aminopyrindans and tetrahydronaphthyridines.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Rafaniello, Alex A

Advisor dc:contributor.advisor

• Gaunt, Matthew

• amine
• azine
• heteroarylation
• indium
• methodology
• organic chemistry

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/281f3f95-f9f7-4642-99df-3542dc0c3505/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.111484

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/372608