Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Applied Biology and Chemical Technology | en_US |
| dc.contributor.advisor | Yu, Wing-yiu Michael (ABCT) | en_US |
| dc.creator | Au, Chi Ming | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/13766 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | Exploration of regio- & stereo-controlled intramolecular amidation of carbon (sp2/sp3) – hydrogen bonds by iron and copper-mediated decomposition of 1,4,2-dioxazol-5-ones towards the development of ligand-controlled regioselective synthesis of γ-/ δ- lactams | en_US |
| dcterms.abstract | Amide bonds are prevalent motifs in many bioactive natural products, pharmaceuticals, and synthetic intermediates. Transition metal-catalyzed direct C–H amidation via metal-nitrenoid transfer offers a straightforward approach for amide bond formation in an atom- and step-economical manner. In recent decades, noble metals (e.g. Pd, Rh, Ir, Ru) have been extensively studied as catalysts for direct C–H amidations. Yet, owing to the natural abundance and environmental sustainability, attention is increasingly drawn to developing earth-abundant metals as catalysts for selective C–H amidation. This research aims to develop catalytic systems based on earth-abundant metals such as iron and copper for catalytic regio- and stereo-controlled direct C–H amidations. | en_US |
| dcterms.abstract | Our investigation began with developing ferrocentium complexes as a new class of catalysts for nitrene transfer reactions. Being a first-row metal, Fe complexes often exist as high-spin complexes, and this poses enormous challenges to catalyst stability due to high lability. In this work, we employed strong-field cyclopentadiene (Cp) ligand to stabilize low-spin Fe center for enhanced catalyst stabilization. With 1,4,2-dioxazol-5-ones derived from arylpropanoic acids as substrate, the ferrocentum [Cp2Fe(III)]+ complex (10 mol%) in CH2Cl2 solvent was found to catalyze decomposition of the dioxazolones to afford 3,4-dihydroquinolin-2(1H)-ones in up to 97% yields. The reaction formally proceeds as regioselective intramolecular acylnitrenoid ortho-C(sp2)–H bond insertion and the competing Curtius-type rearrangement is largely suppressed. Our combined experimental and computational analysis revealed that the intramolecular C(sp2)–H amidation should occur by electrophilic arene addition by reactive Fe(IV)-amidyl radical intermediates. Consistent with the mechanistic study, the regioselectivity (ipso- versus ortho-amidyl radical addition) is influenced by the electronic character on the arenes. The ipso-amidyl radical addition pathway should afford an azaspirocyclohexadienyl radical intermediate. Subsequent radical-polar crossover and 1,2-alkyl migration followed by rearomatization would produce the skeletal rearranged dihydroquinolinone lactams. Our ferrocenium catalysts have been successfully grafted on commercial silica gel to become recyclable heterogeneous catalysts. Conventional construction of 3,4-dihydroquinolin-2(1H)-ones that constitute a unique scaffold in many pharmaceuticals and bioactive compounds are commonly prepared by using stoichiometric toxic reagents with forcing experimental conditions. Our ferrocenium-based catalysis should provide a greener and milder route to this medicinally valuable class of molecules. | en_US |
| dcterms.abstract | Catalyst-controlled regioselective C(sp3)–H functionalization is a topic of fundamental significance. Considerable progress has been made in designing transition metal catalysts to target benzylic or tertiary C–H bonds, in which the target C–H bonds are differentiated by their bond dissociation and steric properties. However, effective differentiation of the methylene C–H bonds on the same hydrocarbon skeleton with similar bond dissociation energies and the steric environment remains a formidable challenge. Our next goal is to develop a catalytic system capable for differentiating γ- and δ- methylene C–H bonds for direct amidation to form γ- or δ-lactams. We found that 1,4,2-dioxazol-5-ones derived from carboxylic acids reacted with [Cu(MeCN)4]BF4 (2.5 mol%) and 2-bromo-1,10-phenanthroline (3.0 mol%) in a HFIP-toluene (4:1) solvent would give the corresponding δ-lactams (up to 75% yields and >20:1 regioselectivities) via the entropically disfavored 1,6-hydrogen atom transfer (HAT) pathway. Yet, employing 2,9-diphenyl-1,10-phenanthroline as ligand in the NFTB-toluene (4:1) solvent (NFTB= 1,1,1,3,3,3-Hexafluoro-2-trifluoromethyl-2-propanol), γ-lactams (up to 62% yields and >10:1 regioselectivities) was produced via the 1,5-HAT at the γ-C–H bonds selectively. It was found that the regioselectivity is largely influenced by the size of the ligand and the substrates. Different solvent systems seem to enhance the regioselectivity via modulating the conformations of the acylnitrene ligand. Radical trapping and Hammett correlation studies suggest that the Cu-nitrenoid intermediate can be best formulated as amidyl radical species. For instance, the 1,n-HAT (n = 5 or 6) afforded the benzyl radicals, which can be trapped by 2,2,6,6-tetramethylpiperidinyloxy (TEMPO). The Cu-catalyzed regioselective C–H amidation should provide insights for the development of regiocontrolled amidation of methylene C–H bonds. | en_US |
| dcterms.abstract | Regiocontrolled alkene difunctionalization is a versatile synthetic route for constructing two different C(sp3)–X bonds (X = C, N, O etc.) within a single operation for forging functionally diversified skeletons. Recently, Chang and co-workers have successfully extended the pentamethylcyclopentadiene (Cp*) Ir-nitrenoid chemistry to stereoselective olefin difunctionalization to synthesize γ-lactams. With an interest in exploring earth-abundant metal-based nitrenoid chemistry, we have extended our study to the Cu-catalyzed stereoselective alkene carboxyamidation. Reacting 1,4,2-dioxazol-5-ones derived from 5-alkenyl carboxylic acids as substrate with [Cu(MeCN)4]BF4 (10 mol%), (4S,4'S)-2,2'-(propane-2,2-diyl)bis(4-(tert-butyl)-4,5-dihydrooxazole) (12 mol%) and benzoic acid (3.0 equiv) in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) afforded oxy-γ-lactams up to 96% yields with threo: erthyro >20:1 selectivity. Consistent with our earlier study, the Cu-nitrene intermediate could be formulated as Cu-amidyl radical. The oxylactamization can be rationalized by the electrophilic radical addition to the C=C bond by the Cu-amidyl radical intermediate via 5-exo-trig cyclization to afford the benzyl radicals. Subsequent radical-polar crossover of the benzyl radicals, followed by nucleophile addition, produced the oxylactam products. The Cu-catalyzed lactamization exhibits excellent functional group tolerance, and nucleophiles derived from pharmaceuticals and bioactive natural products are successfully coupling partners to afford the threo-lactams in >20:1 diastereoselectivities. | en_US |
| dcterms.extent | xxxvi, 666 pages : color illustrations | en_US |
| dcterms.isPartOf | PolyU Electronic Theses | en_US |
| dcterms.issued | 2025 | en_US |
| dcterms.educationalLevel | Ph.D. | en_US |
| dcterms.educationalLevel | All Doctorate | en_US |
| dcterms.LCSH | Transition metal catalysts | en_US |
| dcterms.LCSH | Carbonyl compounds | en_US |
| dcterms.LCSH | Chemical bonds | en_US |
| dcterms.LCSH | Catalysis | en_US |
| dcterms.LCSH | Hong Kong Polytechnic University -- Dissertations | en_US |
| dcterms.accessRights | open access | en_US |
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