{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/317125"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/317125","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Radical methods for the synthesis of aliphatic amines","abstract":"The aliphatic amine motif is a ubiquitous and uniquely important functional group in pharmaceutical agents and the development of ever more efficient synthetic methods for their synthesis is a continuous challenge. This thesis details the development of three new radical reactions for the synthesis of aliphatic amines. Following an introduction to radical chemistry and a summary of previous advances in amine synthesis, chapter 2 will describe a general carbonyl alkylative amination reaction, a successful version of which has been sought for over 70 years. Facilitated by visible light and a silane reducing agent, the operationally straightforward reaction forms tertiary amines via the coupling of aldehydes and secondary amines with alkyl halides. Combining an efficient radical-chain mechanism with the structural and functional diversity of readily available starting materials, the carbonyl alkylative amination provides a flexible strategy for the streamlined synthesis of complex tertiary amines. In chapter 3, an improved carbonyl alkylative amination was sought by replacing the alkyl halide with a more abundant radical precursor. This led to the development of a new carbonyl alkylative amination reaction using tetrachloro N-hydroxyphthalimide esters, prepared from carboxylic acids, in conjunction with inexpensive and environmentally friendly zinc dust instead of the costly silane reducing agent. The use of a carboxylic acid derived nucleophile enabled a broader scope in both amine and nucleophile components and the full potential of this reaction is currently being developed. In chapter 4, a visible light-mediated direct synthesis of N-heterospirocycles is reported. A photocatalyst was employed to reduce an aliphatic iminium ion to the corresponding -amino radical, which was cyclized to afford polar, heteroatom-rich spirocycles. The reaction tolerated a range of polar functional groups and the resulting scaffolds were shown to occupy a promising yet less exploited area of chemical space, making the reaction relevant for fragment-based drug discovery.","abstract_html":"The aliphatic amine motif is a ubiquitous and uniquely important functional group in pharmaceutical agents and the development of ever more efficient synthetic methods for their synthesis is a continuous challenge. This thesis details the development of three new radical reactions for the synthesis of aliphatic amines. Following an introduction to radical chemistry and a summary of previous advances in amine synthesis, chapter 2 will describe a general carbonyl alkylative amination reaction, a successful version of which has been sought for over 70 years. Facilitated by visible light and a silane reducing agent, the operationally straightforward reaction forms tertiary amines via the coupling of aldehydes and secondary amines with alkyl halides. Combining an efficient radical-chain mechanism with the structural and functional diversity of readily available starting materials, the carbonyl alkylative amination provides a flexible strategy for the streamlined synthesis of complex tertiary amines. In chapter 3, an improved carbonyl alkylative amination was sought by replacing the alkyl halide with a more abundant radical precursor. This led to the development of a new carbonyl alkylative amination reaction using tetrachloro N-hydroxyphthalimide esters, prepared from carboxylic acids, in conjunction with inexpensive and environmentally friendly zinc dust instead of the costly silane reducing agent. The use of a carboxylic acid derived nucleophile enabled a broader scope in both amine and nucleophile components and the full potential of this reaction is currently being developed. In chapter 4, a visible light-mediated direct synthesis of N-heterospirocycles is reported. A photocatalyst was employed to reduce an aliphatic iminium ion to the corresponding -amino radical, which was cyclized to afford polar, heteroatom-rich spirocycles. The reaction tolerated a range of polar functional groups and the resulting scaffolds were shown to occupy a promising yet less exploited area of chemical space, making the reaction relevant for fragment-based drug discovery.","abstract_has_math":false,"creators":["Flodén, Nils"],"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":2020,"date_issued":"2020-07-01","date_published":"2020-07-01","updated_at":"2026-07-22T22:24:06Z","subjects":["Radicals","Amines","Photoredox","Visible light"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/00c143dc-326a-4d47-a000-1320d729518c/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000161794519"],"render_values":[{"text":"0000-0001-6179-4519","href":"https://orcid.org/0000-0001-6179-4519","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.64235","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:contributor.sponsor","label":"Sponsor","values":["Gates Cambridge Foundation"]},{"key":"dc:creator","label":"Author","values":["Flodén, Nils"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000161794519"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-07-01"]},{"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/1810/317125"]},{"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":["Radicals","Amines","Photoredox","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/00c143dc-326a-4d47-a000-1320d729518c/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.64235"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fc7bdeb3-422e-4707-9479-cae962257831/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The aliphatic amine motif is a ubiquitous and uniquely important functional group in pharmaceutical agents and the development of ever more efficient synthetic methods for their synthesis is a continuous challenge. 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This led to the development of a new carbonyl alkylative amination reaction using tetrachloro N-hydroxyphthalimide esters, prepared from carboxylic acids, in conjunction with inexpensive and environmentally friendly zinc dust instead of the costly silane reducing agent. The use of a carboxylic acid derived nucleophile enabled a broader scope in both amine and nucleophile components and the full potential of this reaction is currently being developed. In chapter 4, a visible light-mediated direct synthesis of N-heterospirocycles is reported. A photocatalyst was employed to reduce an aliphatic iminium ion to the corresponding -amino radical, which was cyclized to afford polar, heteroatom-rich spirocycles. 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This led to the development of a new carbonyl alkylative amination reaction using tetrachloro N-hydroxyphthalimide esters, prepared from carboxylic acids, in conjunction with inexpensive and environmentally friendly zinc dust instead of the costly silane reducing agent. The use of a carboxylic acid derived nucleophile enabled a broader scope in both amine and nucleophile components and the full potential of this reaction is currently being developed. In chapter 4, a visible light-mediated direct synthesis of N-heterospirocycles is reported. A photocatalyst was employed to reduce an aliphatic iminium ion to the corresponding -amino radical, which was cyclized to afford polar, heteroatom-rich spirocycles. The reaction tolerated a range of polar functional groups and the resulting scaffolds were shown to occupy a promising yet less exploited area of chemical space, making the reaction relevant for fragment-based drug discovery."],"dc:format.checksum.md5":["c887455dd180980552d3953c6d92eac4","353adac0d1ebdfd65ab16480263c3c87"],"dc:identifier.doi":["10.17863/CAM.64235"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fc7bdeb3-422e-4707-9479-cae962257831/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/317125"],"dc:rights":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/00c143dc-326a-4d47-a000-1320d729518c/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:subject":["Radicals","Amines","Photoredox","Visible light"],"dc:title":["Radical methods for the synthesis of aliphatic amines"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:06Z"}