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postgraduate thesis: Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles
Title | Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles |
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Authors | |
Issue Date | 2015 |
Publisher | The 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 |
Abstract | Palladium-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. |
Degree | Doctor of Philosophy |
Subject | Heterocyclic compounds - Synthesis Transition metal catalysts |
Dept/Program | Chemistry |
Persistent Identifier | http://hdl.handle.net/10722/233717 |
HKU Library Item ID | b5610939 |
DC Field | Value | Language |
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dc.contributor.author | Ye, Liu | - |
dc.contributor.author | 葉柳 | - |
dc.date.accessioned | 2016-09-23T23:12:54Z | - |
dc.date.available | 2016-09-23T23:12:54Z | - |
dc.date.issued | 2015 | - |
dc.identifier.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 | - |
dc.identifier.uri | http://hdl.handle.net/10722/233717 | - |
dc.description.abstract | Palladium-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.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Heterocyclic compounds - Synthesis | - |
dc.subject.lcsh | Transition metal catalysts | - |
dc.title | Palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes for synthesis of nitrogen-containing heterocycles | - |
dc.type | PG_Thesis | - |
dc.identifier.hkul | b5610939 | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Chemistry | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_b5610939 | - |
dc.identifier.mmsid | 991014062799703414 | - |