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postgraduate thesis: Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles

TitlePalladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles
Authors
Issue Date2015
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Ye, L. [葉柳]. (2015). Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5610939
AbstractPalladium-catalyzed carboamination (simultaneous formation of C-N and C-C bonds from an olefin) has emerged as an efficient protocol for the synthesis of diversely functionalized N-heterocycles, which are widely displayed in natural products and pharmaceuticals. Compared with the well-documented aminoarylation, aminovinylation and aminoalkynylation, analogous aminoalkylation remains a challenge. This project aims at developing innovative strategies for aminoalkylation to construct a broad array of N-containing heterocycles. An efficient and general palladium-catalyzed intramolecular aminoalkylation of alkenyl aromatic α-halo acetamides with a wide substrate scope under mild conditions has been developed, yielding diverse dihydropyrroloindole derivatives of pharmaceutical interest. Preliminary mechanistic studies suggest that the reaction involves a Pd(0)/Pd(II) catalytic cycle, initiated by oxidative addition of α-halogen of amide with Pd(0) complex. The formation of an unprecedented four-membered-ring Pd(alkyl)amido complex is also supported by ESI-MS analysis. The synthetic utility of this aminoalkylation has been demonstrated by the synthesis of bioactive compounds A, B and C. Then the aminoalkylation reaction has been expanded to the more challenging alkenyl aliphatic α-halo acetamide substrates. This transformation features no requirement for air and moisture sensitive phosphine ligands and provides a straightforward access to a variety of bicyclic pyrrolizidine derivatives. Detailed mechanism studies support the hypothesis that the formation of a four-coordinate intermediate 3-IV is crucial for the realization of this transformation. An isotopic labeling experiment indicates that the aminopalladation proceeds through syn-insertion of alkene into Pd-N bond. The application of this aminoalkylation reaction to construct bicyclic isoxazolidines from α-halo oxy-acetamides has been explored. The reaction proceeds well at room temperature for α-iodo substrates. In addition, α-bromo and α-chloro substrates are also compatible, affording the desired products in good yields with moderate diastereoselectivity. The observation of different effects from externally added phosphine ligands indicates a distinct catalytic cycle, which may involve an initial aminopalladation followed by bimetallic transmetallation or oxidative addition. This tandem cyclization may offer a novel route to natural products and bioactive compounds containing this core. Finally, the enantioselective intramolecular aminoalkylation for the construction of chiral bicyclic isoxazolidines has been attempted. After screening of a variety of reaction parameters and a series of SPINOL-based ligands, a catalytic system has been disclosed, which utilizes 7 mol% Pd(TFA)2, 20 mol% (R)-Siphos-PE, 300 mol% sodium bromide and 100 mol% sodium carbonate. The desired product can be obtained in 70% yield with 60% enantiomeric excess. A general structure-activity-relationship (SAR) for SPINOL-based ligands is obtained, which provides a platform for further modification.
DegreeDoctor of Philosophy
SubjectHeterocyclic compounds - Synthesis
Transition metal catalysts
Dept/ProgramChemistry
Persistent Identifierhttp://hdl.handle.net/10722/233717

 

DC FieldValueLanguage
dc.contributor.authorYe, Liu-
dc.contributor.author葉柳-
dc.date.accessioned2016-09-23T23:12:54Z-
dc.date.available2016-09-23T23:12:54Z-
dc.date.issued2015-
dc.identifier.citationYe, L. [葉柳]. (2015). Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5610939-
dc.identifier.urihttp://hdl.handle.net/10722/233717-
dc.description.abstractPalladium-catalyzed carboamination (simultaneous formation of C-N and C-C bonds from an olefin) has emerged as an efficient protocol for the synthesis of diversely functionalized N-heterocycles, which are widely displayed in natural products and pharmaceuticals. Compared with the well-documented aminoarylation, aminovinylation and aminoalkynylation, analogous aminoalkylation remains a challenge. This project aims at developing innovative strategies for aminoalkylation to construct a broad array of N-containing heterocycles. An efficient and general palladium-catalyzed intramolecular aminoalkylation of alkenyl aromatic α-halo acetamides with a wide substrate scope under mild conditions has been developed, yielding diverse dihydropyrroloindole derivatives of pharmaceutical interest. Preliminary mechanistic studies suggest that the reaction involves a Pd(0)/Pd(II) catalytic cycle, initiated by oxidative addition of α-halogen of amide with Pd(0) complex. The formation of an unprecedented four-membered-ring Pd(alkyl)amido complex is also supported by ESI-MS analysis. The synthetic utility of this aminoalkylation has been demonstrated by the synthesis of bioactive compounds A, B and C. Then the aminoalkylation reaction has been expanded to the more challenging alkenyl aliphatic α-halo acetamide substrates. This transformation features no requirement for air and moisture sensitive phosphine ligands and provides a straightforward access to a variety of bicyclic pyrrolizidine derivatives. Detailed mechanism studies support the hypothesis that the formation of a four-coordinate intermediate 3-IV is crucial for the realization of this transformation. An isotopic labeling experiment indicates that the aminopalladation proceeds through syn-insertion of alkene into Pd-N bond. The application of this aminoalkylation reaction to construct bicyclic isoxazolidines from α-halo oxy-acetamides has been explored. The reaction proceeds well at room temperature for α-iodo substrates. In addition, α-bromo and α-chloro substrates are also compatible, affording the desired products in good yields with moderate diastereoselectivity. The observation of different effects from externally added phosphine ligands indicates a distinct catalytic cycle, which may involve an initial aminopalladation followed by bimetallic transmetallation or oxidative addition. This tandem cyclization may offer a novel route to natural products and bioactive compounds containing this core. Finally, the enantioselective intramolecular aminoalkylation for the construction of chiral bicyclic isoxazolidines has been attempted. After screening of a variety of reaction parameters and a series of SPINOL-based ligands, a catalytic system has been disclosed, which utilizes 7 mol% Pd(TFA)2, 20 mol% (R)-Siphos-PE, 300 mol% sodium bromide and 100 mol% sodium carbonate. The desired product can be obtained in 70% yield with 60% enantiomeric excess. A general structure-activity-relationship (SAR) for SPINOL-based ligands is obtained, which provides a platform for further modification.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshHeterocyclic compounds - Synthesis-
dc.subject.lcshTransition metal catalysts-
dc.titlePalladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles-
dc.typePG_Thesis-
dc.identifier.hkulb5610939-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineChemistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b5610939-

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