| Author: | Yeung, Yiu Wai |
| Title: | Exploration of site-selective carbon(sp3)- nitrogen cross-coupling reactions by Ru(II)-catalyzed γ-selective amidation of methylene C-H bonds of alkenes with sulfonyl azides and 1,4,2-dioxazol-5-ones and Cu-catalyzed hydrogenative cross-coupling of α-diazocarbonyl compounds and O-benzoyl hydroxylamines |
| Advisors: | Yu, Wing-yiu Michael (ABCT) |
| Degree: | Ph.D. |
| Year: | 2023 |
| Subject: | Amines Amines -- Synthesis Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | xxxix, 374 pages : color illustrations |
| Language: | English |
| Abstract: | Aliphatic amines are ubiquitous in natural products and pharmaceuticals. Traditional construction of amine often required forcing conditions such as high temperature and use of stoichiometric toxic chemicals, which limited amine complexity. In recent decades, transition metal-catalyzed C-N bond formation has proven to be an effective route for synthesizing amines under mild conditions. In particular, electrophilic amination employing umpolung strategy has greatly enhanced the synthetic complexity of amines. The first part of the thesis explored a Ru(II)-catalyzed site-selective isomerization and γ-methylene C-H amidation reaction. To begin, we treated 4-phenyl-1-butene with tosyl azide in the presence of [(p-cymene)RuCl₂]₂, LiOAc and AgNTf₂. To our surprise, a mixture of regioisomers (rr = 1:1) was obtained in 90% combined yield. However, one of regioisomers was theoretically inaccessible from terminal olefin. Careful examination of the crude reaction mixture revealed the Ru catalyst possess a fast and reversible CMD process which give the internal alkene before amidation occurs. After a series of optimization, a protocol with isomerization/amidation cascade was able to give the γ-selective styryl sulfonamide up to 87% yield and >20:1 regioselectivity. It is suggested the highly regioselective styryl sulfonamide formation involve an SN1-type isomerization pathway. Next, we turned to explore a Cu-catalyzed hydroamination reaction of diazocarbonyl compounds for the synthesis of α-amino acid derivatives. Treating ethyl α-diazoheptanoate with morpholino benzoate in the presence of Cu(OAc)₂ and PMHS successfully give the coupling product in 20% yield. After optimization, the desired α-amino ester was successfully obtained up to 97% yield. The synthetic utility was further explored to the synthesis of anti-platlet drug, (±)-Clopidogrel, under mild conditions. Radical trap experiments with BHT, DMPO and TEMPO was conducted, and morpholine adducts with BHT and DMPO were isolated and characterized. The result suggests nitrogen-centered radical was generated as one of the intermediate in the catalytic reaction. The final part of the thesis revealed a Cu-catalyzed cross electrophile coupling reaction between diazocarbonyl compounds and 1,4,2-dioxazol-5-one. Initial reaction treating 3-phenyl-1,4,2-dioxazol-5-one with ethyl α-diazophenylacetate in the presence of CuOAc/dtbbpy, LiOtBu and PMHS gave 20% of target amide. After optimization, the coupling reaction successfully gave the corresponding amide up to 95% yield. Mechanistic experiments suggested a nitrene insertion to CuH formed a Cu-amidate intermediate, subsequent carbene insertion to Cu-amido intermediate give the corresponding amide. |
| Rights: | All rights reserved |
| Access: | open access |
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