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Title: Exploration of regioselective cyclization of dioxazolones and carbonylhydrazones by transition metal-mediated C-H bond activation and development of metal-free photocatalytic radical coupling of α-diazoacetates
Authors: Chan, Chun Ming
Degree: Ph.D.
Issue Date: 2019
Abstract: The development of catalytic C-N bonds formation is one of the major research topics in synthetic chemistry owing to the ubiquity of amino groups in natural products, synthetic intermediates and pharmaceutical agents. The introduction of amino functions in a controllable manner is critical for synthetic applications. In this research, we aim to develop innovative and practical catalytic cross-coupling reactions with some readily available or easily prepared substrates, such as dioxazolones, carbonylhydrazones, α-diazoesters, alkynes, and N-hydroxyphthalimide esters for the synthesis of chiral γ-lactams, pyrroles and hydrazones via regioselective C-N bond formations. Chiral γ-lactams are prevalent motifs in pharmaceuticals and bioactive natural products and transition-metal catalyzed enantioselective direct C-H amidation of hydrocarbon feedstocks offers a direct access to them. While benzylic and allylic C-H bond amidation are well-documented with sulfonylnitrene insertion using hypervalent iodine(III) or with sulfonylazides as precursors for sulfonylnitrene formation, enantioselective nitrene insertion to C(sp3)-H bonds to form chiral γ-lactams remain a formidable challenge. The first part of this thesis describes the Ru-catalyzed enantioselective annulation of 1,4,2-dioxazol-5-ones to furnish γ-lactams in up to 97% yield and 98% ee via intramolecular carbonylnitrene C-H insertion. By employing chiral diphenylethylene diamine (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the reactions occur with remarkable chemo- and enantioselectivities; the competing Curtius-type rearrangement was largely suppressed. Enantioselective nitrene insertion to allylic/propargylic C-H bonds was also achieved with remarkable tolerance to the C=C and C≡C bonds. This asymmetric Ru-catalyzed C-H bond amidation strategy represents a powerful tool for easy transformation of hydrocarbon feedstocks to chiral γ-lactams core, which can be derived to high valued pharmaceutical.
Pyrroles are privileged heterocyclic scaffolds present in many pharmaceutical products and functional materials and the synthesis of pyrroles received considerable interest. However, examples for pyrrole (especially NH-pyrroles) synthesis by catalytic regioselective C(sp3)-H bond functionalization are sparse in the literature. The second part of this thesis disclosed the rhodium(III)-catalyzed cycloaddition of N-tert-butoxycarbonylhydrazones with internal alkynes for the synthesis of NH-pyrrole. Different from other cross-coupling approaches, the use of oxidative directing group offers direct access to NH-pyrroles while many other reports require protection and deprotection for the amino group. This reaction features a regioselective α-imino alkyl C(sp3)-H bond functionalization resulting in selective formation of highly functionalized NH-free pyrroles. N-tert-Butoxycarbonyl (N-Boc) was employed as the oxidizing directing group and it is critical for achieving the observed pyrrole formation versus the isoquinoline formation. We hypothesized that a prior tautomerization of the N-Boc-hydrazones to enamines should occur, followed by a regioselective C(sp2)-H cleavage to form a putative five-membered rhodacycle in our mechanism. While the subsequent coupling of the rhodacycle with the alkynes would afford the pyrrole products. This operationally simple method provides an easy alternative for the formation of pyrroles. Recently, the revival of radical chemistry in organic synthesis has promoted our interest in developing metal-free C-N bond construction under mild conditions. Diazo compounds are well-known as versatile cross-coupling partners for metal-catalyzed transformations. The diazo substrates react with transition metal catalysts to generate the metal carbene intermediate, which undergoes rapid migratory insertion to form a C-C bond. Yet, only a few examples show that the retention of the diazo functionality is possible for cross-coupling reaction. In this regard, where we explored a metal-free C-N bond formation by photoredox cross-coupling reaction. We found that Rose Bengal can catalyze diazo-radical-coupling reaction for the synthesis of N-alkylhydrazones under the irradiation of yellow LEDs with α-diazoesters and alkyl N-hydroxyphthalimide esters. This reaction is fundamentally different from classical diazo coupling reactions and the dinitrogen group is retained for C-N bond formation. Since N-hydroxyphthalimide esters can be easily prepared from carboxylic acids, this photoredox reaction provides a practical approach to furnish hydrazone derivatives under mild conditions and opens the possibility for direct modification of carboxylic acids for late-stage functionalization.
Subjects: Hong Kong Polytechnic University -- Dissertations
Chemical reactions
Pages: xxxiii, 632 pages : color illustrations
Appears in Collections:Thesis

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