{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/373370"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/373370","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Smith, Milo"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Gaunt, Matthew"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05-07","date_published":"2024-05-07","updated_at":"2026-07-22T22:24:14Z","subjects":["Amines","Imines","Photocatalysis","Photochemistry","Photoredox","Radicals","Visible light"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a57b7572-4a7e-4950-8599-7a431d355ad6/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000284039636"],"render_values":[{"text":"0000-0002-8403-9636","href":"https://orcid.org/0000-0002-8403-9636","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.111824","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Gaunt, Matthew"]},{"key":"dc:creator","label":"Author","values":["Smith, Milo"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000284039636"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-05-07"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/373370"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Amines","Imines","Photocatalysis","Photochemistry","Photoredox","Radicals","Visible light"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a57b7572-4a7e-4950-8599-7a431d355ad6/download","https://www.rioxx.net/licenses/all-rights-reserved/"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2025-09-11"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.111824"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/71ba9e7e-6f6c-475a-99d3-4211697dbf6f/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The efficient assembly of complex molecules from cheap and abundant feedstock materials is a central goal of organic synthesis. 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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. 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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. 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