{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/115677"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/115677","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Late stage oxidative C(sp3)–H alkylation and arylation","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","abstract_has_math":false,"creators":["Quevedo, Raundi Evangeline"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["White, Maria Christina","Denmark, Scott E","Sarlah, David","Murphy, Catherine J"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-05","date_published":"2022-05","updated_at":"2026-07-22T22:24:55Z","subjects":["C-H functionalisation","Alkylation","Methylation","Arylation","Saturated heterocycle functionalisation"],"languages":["en","eng"],"rights":["Copyright 2022 Raundi Quevedo"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/115677","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["White, Maria Christina","Denmark, Scott E","Sarlah, David","Murphy, Catherine J"]},{"key":"dc:creator","label":"Author","values":["Quevedo, Raundi Evangeline"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-05","2022-04-05"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["C-H functionalisation","Alkylation","Methylation","Arylation","Saturated heterocycle functionalisation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2022 Raundi Quevedo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/115677"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","The student, Raundi Quevedo, accepted the attached license on 2022-03-29 at 07:58.","The student, Raundi Quevedo, submitted this Dissertation for approval on 2022-03-29 at 08:06.","This Dissertation was approved for publication on 2022-04-05 at 12:16.","DSpace SAF Submission Ingestion Package generated from Vireo submission #17558 on 2022-11-11 at 12:18:50","The introduction of small alkyl and aryl groups, such as methyl, cyclopropyl, or phenyl, onto drug scaffolds can significantly alter the pharmacokinetic profile of a molecule in terms of drug potency, metabolism, binding and lipophilicity. Some of these effects are most notable when the change occurs alpha (a) to heteroatoms such as nitrogen or oxygen. The fine-tuning of such properties is of great interest to medicinal chemists in the drug discovery process, where the optimization of these drug characteristics can result in a potential lead candidate that will progress into clinical development. However, de novo syntheses are often required from medicinal chemists to explore this large chemical space. These syntheses tend to be long and costly, usually because these organic molecules are constructed by manipulating functionality already present on the molecule to build up molecular complexity. Instead of proceeding via functional group manipulations, C(sp3)–H activation is a more recent development that enables chemists to target ubiquitous C–H bonds that were typically viewed as inert, obviating the need for pre-existing functionality. The challenge resides in developing catalysts and reagents that are reactive enough to functionalize these high energy C(sp3)–H bonds, but do so with high selectivity, predictability and tolerance of sensitive, electrophilic functionalities. This work describes my efforts in developing methods that can introduce a variety of alkyl and aryl groups directly from C(sp3)–H bonds a to nitrogen and oxygen in late-stage drug scaffolds with proximal epimerizable stereocenters, electrophilic functionalities, basic nitrogen moieties and aromatic groups. The first chapter of this thesis will focus on the development of an oxidative C(sp3)–H methylation. Many scientists have observed that the introduction of methyl groups onto drug scaffolds, especially at positions a to heteroatoms, can often lead to significant potency boosts. These boosts, ranging from 2- to 2000-fold, cannot always be rationalized and are often observed experimentally. Accordingly, scientists have coined the term “magic methyl effect” to describe this. In the last five years, methods that focused on methylation from C(sp3)–H bonds proceeded via a nucleophilic, metalated intermediate that reacted with an electrophilic methyl source. These methods were often limited in their scope, with no or little examples of substrates with electrophilic functionalities, basic nitrogen moieties, dissymmetric cores or proximal epimerizable stereocenters. This limits their usage on late-stage drug candidates. This work focused on developing a method that proceeded via a hemiaminal or hemiacetal intermediate generated by a site- and chemoselective MnCF3PDP catalyst. Subsequent exposure to fluoride or Lewis acid activators generated an electrophilic iminium or oxonium ion intermediate that could then react with trimethylaluminum. Low catalyst loadings (200:1 substrate to catalyst ratio) enabled me to suppress deleterious aromatic oxidation and overoxidation of the hemiaminal to imides, while highlighting new tolerance of electron-rich and electron-neutral aromatics and heteroaromatics. This, combined with a modestly Lewis acidic methyl nucleophile, enabled the methylation of over 8 pharmaceutically relevant molecules that represent a plethora of functionality, including substrates where the magic methyl effect was observed The second chapter of this thesis will focus on the introduction of a variety of alkyl and aryl groups a to heteroatoms. As seen with the magic methyl effect, small groups such as cyclopropyl or phenyl can modulate the pharmacokinetic profile of a drug in sometimes beneficial ways. Most changes have focused on changes in lipophilicity, binding, metabolism and potency. Previously established methods to functionalize C(sp3)–H still rely on a nucleophilic metalated intermediate, and either lack or have not demonstrated application in late-stage contexts. In addition to the limitations aforementioned in the methylation case, there are also issues with both overfunctionalization to dialkylated products and with regioisomeric mixtures. Many of these issues could be resolved via a highly site-selective MnCF3PDP-mediated hydroxylation. An additional challenge was then to determine what nucleophilic source would be used as an alkylating reagent. Trialkyl- and triarylaluminum reagents are not commercially available, difficult to synthesize, and often result in elimination or degradation products. Upon extensive screening, I discovered an organocopper reagent that could selectively functionalize iminium and oxonium ions, with little to no elimination or attack of other electrophilic moieties on the drug scaffold. Key to this reactivity was the discovery of new nitrogen-protecting groups that were compatible with our catalyst. While the methylation had previously been limited to nosyl motifs, carbamates such as the tert-butoxycarbonyl (Boc) group were now tolerated, greatly improving the generality and scope of this method. The change resulted in faster C(sp3)–H hydroxylation than protecting group hydrolysis. I demonstrated that many heterocyclic cores, including challenging azetidines, could be functionalized with a variety of sp3 and sp2 nucleophiles. I also focused on demonstrating how this method could be used in broader screening contexts by synthesizing different desloratadine derivatives."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Late stage oxidative C(sp3)–H alkylation and arylation"]}]}],"canonical_facts":{"dc:contributor":["White, Maria Christina","Denmark, Scott E","Sarlah, David","Murphy, Catherine J"],"dc:creator":["Quevedo, Raundi Evangeline"],"dc:date":["2022-05","2022-04-05"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2024-05-01","The student, Raundi Quevedo, accepted the attached license on 2022-03-29 at 07:58.","The student, Raundi Quevedo, submitted this Dissertation for approval on 2022-03-29 at 08:06.","This Dissertation was approved for publication on 2022-04-05 at 12:16.","DSpace SAF Submission Ingestion Package generated from Vireo submission #17558 on 2022-11-11 at 12:18:50","The introduction of small alkyl and aryl groups, such as methyl, cyclopropyl, or phenyl, onto drug scaffolds can significantly alter the pharmacokinetic profile of a molecule in terms of drug potency, metabolism, binding and lipophilicity. Some of these effects are most notable when the change occurs alpha (a) to heteroatoms such as nitrogen or oxygen. The fine-tuning of such properties is of great interest to medicinal chemists in the drug discovery process, where the optimization of these drug characteristics can result in a potential lead candidate that will progress into clinical development. However, de novo syntheses are often required from medicinal chemists to explore this large chemical space. These syntheses tend to be long and costly, usually because these organic molecules are constructed by manipulating functionality already present on the molecule to build up molecular complexity. Instead of proceeding via functional group manipulations, C(sp3)–H activation is a more recent development that enables chemists to target ubiquitous C–H bonds that were typically viewed as inert, obviating the need for pre-existing functionality. The challenge resides in developing catalysts and reagents that are reactive enough to functionalize these high energy C(sp3)–H bonds, but do so with high selectivity, predictability and tolerance of sensitive, electrophilic functionalities. This work describes my efforts in developing methods that can introduce a variety of alkyl and aryl groups directly from C(sp3)–H bonds a to nitrogen and oxygen in late-stage drug scaffolds with proximal epimerizable stereocenters, electrophilic functionalities, basic nitrogen moieties and aromatic groups. The first chapter of this thesis will focus on the development of an oxidative C(sp3)–H methylation. Many scientists have observed that the introduction of methyl groups onto drug scaffolds, especially at positions a to heteroatoms, can often lead to significant potency boosts. These boosts, ranging from 2- to 2000-fold, cannot always be rationalized and are often observed experimentally. Accordingly, scientists have coined the term “magic methyl effect” to describe this. In the last five years, methods that focused on methylation from C(sp3)–H bonds proceeded via a nucleophilic, metalated intermediate that reacted with an electrophilic methyl source. These methods were often limited in their scope, with no or little examples of substrates with electrophilic functionalities, basic nitrogen moieties, dissymmetric cores or proximal epimerizable stereocenters. This limits their usage on late-stage drug candidates. This work focused on developing a method that proceeded via a hemiaminal or hemiacetal intermediate generated by a site- and chemoselective MnCF3PDP catalyst. Subsequent exposure to fluoride or Lewis acid activators generated an electrophilic iminium or oxonium ion intermediate that could then react with trimethylaluminum. Low catalyst loadings (200:1 substrate to catalyst ratio) enabled me to suppress deleterious aromatic oxidation and overoxidation of the hemiaminal to imides, while highlighting new tolerance of electron-rich and electron-neutral aromatics and heteroaromatics. This, combined with a modestly Lewis acidic methyl nucleophile, enabled the methylation of over 8 pharmaceutically relevant molecules that represent a plethora of functionality, including substrates where the magic methyl effect was observed The second chapter of this thesis will focus on the introduction of a variety of alkyl and aryl groups a to heteroatoms. As seen with the magic methyl effect, small groups such as cyclopropyl or phenyl can modulate the pharmacokinetic profile of a drug in sometimes beneficial ways. Most changes have focused on changes in lipophilicity, binding, metabolism and potency. Previously established methods to functionalize C(sp3)–H still rely on a nucleophilic metalated intermediate, and either lack or have not demonstrated application in late-stage contexts. In addition to the limitations aforementioned in the methylation case, there are also issues with both overfunctionalization to dialkylated products and with regioisomeric mixtures. Many of these issues could be resolved via a highly site-selective MnCF3PDP-mediated hydroxylation. An additional challenge was then to determine what nucleophilic source would be used as an alkylating reagent. Trialkyl- and triarylaluminum reagents are not commercially available, difficult to synthesize, and often result in elimination or degradation products. Upon extensive screening, I discovered an organocopper reagent that could selectively functionalize iminium and oxonium ions, with little to no elimination or attack of other electrophilic moieties on the drug scaffold. Key to this reactivity was the discovery of new nitrogen-protecting groups that were compatible with our catalyst. While the methylation had previously been limited to nosyl motifs, carbamates such as the tert-butoxycarbonyl (Boc) group were now tolerated, greatly improving the generality and scope of this method. The change resulted in faster C(sp3)–H hydroxylation than protecting group hydrolysis. I demonstrated that many heterocyclic cores, including challenging azetidines, could be functionalized with a variety of sp3 and sp2 nucleophiles. I also focused on demonstrating how this method could be used in broader screening contexts by synthesizing different desloratadine derivatives."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/115677"],"dc:language":["en","eng"],"dc:rights":["Copyright 2022 Raundi Quevedo"],"dc:subject":["C-H functionalisation","Alkylation","Methylation","Arylation","Saturated heterocycle functionalisation"],"dc:title":["Late stage oxidative C(sp3)–H alkylation and arylation"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:55Z"}