{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/125810"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/125810","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Expanding the scope of allylic C—H aminations via electrophilic palladium(II) catalysis","abstract":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","abstract_html":"Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","abstract_has_math":false,"creators":["Budaitis, Brenna Gerette"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["White, Christina","Sarlah, David","Hergenrother, Paul H","Mirica, Liviu"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-07-11","date_published":"2024-07-11","updated_at":"2026-07-22T22:25:02Z","subjects":["Allylic C—h Amination","Palladium(ii) Catalysis","Terminal Olefins","Secondary Amines","Synthesis Of Tertiary Amines","Synthesis Of Pharmaceuticals"],"languages":["en","eng"],"rights":["Copyright 2024 Brenna Budaitis"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/125810","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["White, Christina","Sarlah, David","Hergenrother, Paul H","Mirica, Liviu"]},{"key":"dc:creator","label":"Author","values":["Budaitis, Brenna Gerette"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-07-11","2024-08"]},{"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":["Allylic C—h Amination","Palladium(ii) Catalysis","Terminal Olefins","Secondary Amines","Synthesis Of Tertiary Amines","Synthesis Of Pharmaceuticals"]}]},{"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 2024 Brenna Budaitis"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/125810"]}]},{"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 2026-08-01","The student, Brenna Budaitis, accepted the attached license on 2024-07-10 at 00:24.","The student, Brenna Budaitis, submitted this Dissertation for approval on 2024-07-10 at 02:14.","This Dissertation was approved for publication on 2024-07-11 at 11:26.","DSpace SAF Submission Ingestion Package generated from Vireo submission #21033 on 2025-02-04 at 21:25:47","Olefins are readily accessible and robust feedstock commodities that serve as significant building blocks in synthetic transformations. Traditional electrophiles (alkyl halides and carbonyls) in well-established classic transformations are derived from olefins and more recently, these hydrocarbons have been demonstrated as effective coupling partners in the development of new methodologies – including metal-catalyzed aza-Wacker reactions, hydroaminations, as well as light and electrochemical mediated olefin functionalizations. Tertiary aliphatic and aryl amines are ubiquitous in pharmaceuticals, and the development of C(sp3)—N aminations that cross-couples readily accessible secondary amines and olefin hydrocarbons provides an attractive approach in the syntheses of these important compounds. Current metal-mediated C—H aminations, however, are largely limited to the coupling of specialized amine nucleophiles (e.g. protected amines, electron deficient amines) or activated olefins (e.g. allylbenzene derivatives) in excess amounts to furnish secondary or primary amine products. Subsequent synthetic manipulations (e.g. deprotection followed by N-alkylation) are oftentimes required to access tertiary amine derivatives. Basic secondary amine nucleophiles under such processes have a high propensity to bind to metal catalysts and inhibit key steps in the catalytic cycle, such as metal-mediated C—H cleavage, rendering the direct access to tertiary amines via electrophilic metal-catalyzed C—H amination a longstanding challenge. This thesis describes the efforts in the development of sulfoxide-oxazoline-palladium(II) (SOX·Pd(OAc)2) mediated allylic C—H aminations for the synthesis of allylic tertiary amine products in excellent reactivities and selectivities guided by mechanistic experiments, enabling the efficient syntheses of pharmaceuticals and derivatives. The first chapter of this dissertation describes the development and application of a SOX·Pd(OAc)2/Brønsted acid catalyzed allylic C—H amination cross-coupling of secondary amine·BF3 complexes with terminal olefins to furnish tertiary aliphatic amines. Whereas stoichiometric amounts of basic amine are deleterious to metal-mediated C—H amination processes, we proposed that small concentrations of basic amines may co-exist with the electrophilic metal and thereby foster productive reactivity. Key to this catalysis was the development of an autoregulatory mechanism that couples the release of free amine nucleophile from amine·BF3 pronucleophiles with catalyst turnover, enabling allylic C—H amination without inhibiting metal-mediated heterolytic C—H cleavage. This method features 48 amines (10 medicinally relevant cores) and 34 olefins (housing electrophilic functionality) to furnish 81 tertiary amines (including 12 drugs and 10 complex drug derivatives) with high functional group tolerance and excellent regio- and stereochemistry (>20:1 E/Z, >20:1 linear:branched). We anticipate for this strategy to empower broad applicability of basic amines in other electrophilic metal-mediated aminations. The second chapter of this dissertation describes the development and application of a SOX·Pd(OAc)2/Brønsted acid catalyzed C(sp3)—N(sp2) cross-coupling of terminal olefin electrophiles and secondary aryl amines nucleophiles. Traditional approaches in the synthesis of N,N-dialkylated aryl amines are challenging in result to the coupling of “soft” aryl amine nucleophiles with “hard” pre-oxidized electrophiles. We proposed that the cross-coupling of anilines with olefins, proceeding via a metal-π-allyl intermediate, may afford higher reactivity due to the better-matched polarizabilities of these “soft” amine nucleophiles with “soft” palladium(II)-π-allyl electrophiles. Spectroscopic studies revealed that the relatively softer nature of secondary aryl amine nucleophiles affords diminished and reversible binding to the palladium(II)-metal relative to aliphatic secondary amines, enabling the efficient coupling of free N—H aryl amine nucleophiles to furnish tertiary aryl amines with a weaker palladium(II)-binding affinity. The electronically and sterically diverse aryl amine scope (42 examples) and olefin scope (28 examples) demonstrating high functional group compatibility, as well as the robust and mild conditions of this C—H to C—N amination facilitated late-stage fragment couplings in the synthesis of pharmaceuticals and derivatives (13 examples) in excellent reactivity and selectivities (>20:1 E/Z, >20:1 lieanr:branched). Mechanistic studies support a divergent mechanism from the previous N-triflyl amine nucleophiles used in SOX·Pd(OAc)2 catalysis, in which aryl amines functionalize as the neutral amine and proceed a facile functionalization event facilitated by an electrostatic activation of the π-allyl-Pd(SOX) intermediate by the phosphoric acid additive."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Expanding the scope of allylic C—H aminations via electrophilic palladium(II) catalysis"]}]}],"canonical_facts":{"dc:contributor":["White, Christina","Sarlah, David","Hergenrother, Paul H","Mirica, Liviu"],"dc:creator":["Budaitis, Brenna Gerette"],"dc:date":["2024-07-11","2024-08"],"dc:description":["Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-08-01","The student, Brenna Budaitis, accepted the attached license on 2024-07-10 at 00:24.","The student, Brenna Budaitis, submitted this Dissertation for approval on 2024-07-10 at 02:14.","This Dissertation was approved for publication on 2024-07-11 at 11:26.","DSpace SAF Submission Ingestion Package generated from Vireo submission #21033 on 2025-02-04 at 21:25:47","Olefins are readily accessible and robust feedstock commodities that serve as significant building blocks in synthetic transformations. Traditional electrophiles (alkyl halides and carbonyls) in well-established classic transformations are derived from olefins and more recently, these hydrocarbons have been demonstrated as effective coupling partners in the development of new methodologies – including metal-catalyzed aza-Wacker reactions, hydroaminations, as well as light and electrochemical mediated olefin functionalizations. Tertiary aliphatic and aryl amines are ubiquitous in pharmaceuticals, and the development of C(sp3)—N aminations that cross-couples readily accessible secondary amines and olefin hydrocarbons provides an attractive approach in the syntheses of these important compounds. Current metal-mediated C—H aminations, however, are largely limited to the coupling of specialized amine nucleophiles (e.g. protected amines, electron deficient amines) or activated olefins (e.g. allylbenzene derivatives) in excess amounts to furnish secondary or primary amine products. Subsequent synthetic manipulations (e.g. deprotection followed by N-alkylation) are oftentimes required to access tertiary amine derivatives. Basic secondary amine nucleophiles under such processes have a high propensity to bind to metal catalysts and inhibit key steps in the catalytic cycle, such as metal-mediated C—H cleavage, rendering the direct access to tertiary amines via electrophilic metal-catalyzed C—H amination a longstanding challenge. This thesis describes the efforts in the development of sulfoxide-oxazoline-palladium(II) (SOX·Pd(OAc)2) mediated allylic C—H aminations for the synthesis of allylic tertiary amine products in excellent reactivities and selectivities guided by mechanistic experiments, enabling the efficient syntheses of pharmaceuticals and derivatives. The first chapter of this dissertation describes the development and application of a SOX·Pd(OAc)2/Brønsted acid catalyzed allylic C—H amination cross-coupling of secondary amine·BF3 complexes with terminal olefins to furnish tertiary aliphatic amines. Whereas stoichiometric amounts of basic amine are deleterious to metal-mediated C—H amination processes, we proposed that small concentrations of basic amines may co-exist with the electrophilic metal and thereby foster productive reactivity. Key to this catalysis was the development of an autoregulatory mechanism that couples the release of free amine nucleophile from amine·BF3 pronucleophiles with catalyst turnover, enabling allylic C—H amination without inhibiting metal-mediated heterolytic C—H cleavage. This method features 48 amines (10 medicinally relevant cores) and 34 olefins (housing electrophilic functionality) to furnish 81 tertiary amines (including 12 drugs and 10 complex drug derivatives) with high functional group tolerance and excellent regio- and stereochemistry (>20:1 E/Z, >20:1 linear:branched). We anticipate for this strategy to empower broad applicability of basic amines in other electrophilic metal-mediated aminations. The second chapter of this dissertation describes the development and application of a SOX·Pd(OAc)2/Brønsted acid catalyzed C(sp3)—N(sp2) cross-coupling of terminal olefin electrophiles and secondary aryl amines nucleophiles. Traditional approaches in the synthesis of N,N-dialkylated aryl amines are challenging in result to the coupling of “soft” aryl amine nucleophiles with “hard” pre-oxidized electrophiles. We proposed that the cross-coupling of anilines with olefins, proceeding via a metal-π-allyl intermediate, may afford higher reactivity due to the better-matched polarizabilities of these “soft” amine nucleophiles with “soft” palladium(II)-π-allyl electrophiles. Spectroscopic studies revealed that the relatively softer nature of secondary aryl amine nucleophiles affords diminished and reversible binding to the palladium(II)-metal relative to aliphatic secondary amines, enabling the efficient coupling of free N—H aryl amine nucleophiles to furnish tertiary aryl amines with a weaker palladium(II)-binding affinity. The electronically and sterically diverse aryl amine scope (42 examples) and olefin scope (28 examples) demonstrating high functional group compatibility, as well as the robust and mild conditions of this C—H to C—N amination facilitated late-stage fragment couplings in the synthesis of pharmaceuticals and derivatives (13 examples) in excellent reactivity and selectivities (>20:1 E/Z, >20:1 lieanr:branched). Mechanistic studies support a divergent mechanism from the previous N-triflyl amine nucleophiles used in SOX·Pd(OAc)2 catalysis, in which aryl amines functionalize as the neutral amine and proceed a facile functionalization event facilitated by an electrostatic activation of the π-allyl-Pd(SOX) intermediate by the phosphoric acid additive."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/125810"],"dc:language":["en","eng"],"dc:rights":["Copyright 2024 Brenna Budaitis"],"dc:subject":["Allylic C—h Amination","Palladium(ii) Catalysis","Terminal Olefins","Secondary Amines","Synthesis Of Tertiary Amines","Synthesis Of Pharmaceuticals"],"dc:title":["Expanding the scope of allylic C—H aminations via electrophilic palladium(II) catalysis"],"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":"2026-07-22T22:25:02Z"}