| Author: | Chen, Zicong |
| Title: | Development of effective palladium catalytic systems for the transformation of Csp²‒O and Csp²‒CI bonds |
| Advisors: | So, Chau Ming (ABCT) |
| Degree: | Ph.D. |
| Year: | 2022 |
| Subject: | Palladium catalysts Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | xiii, 673 pages : color illustrations |
| Language: | English |
| Abstract: | Palladium-catalyzed cross-coupling reaction has emerged as one of the most powerful tools in modern organic synthesis. One of the major explorations of this field is expanding the scope of substrates and products. Recently, increasing studies have been directed to search for coupling reagents that are of structural diversity and environmentally benign. O-based electrophiles are promising choices due to their abundancy and facile preparation from natural sources, for instance, phenolic electrophiles and enol electrophiles. However, the utilization of new substrates requires the development of effective catalytic systems. This thesis focuses on: (1) palladium-catalyzed cross-coupling reactions of O-based electrophiles through C-O bond activation; and (2) the chemoselective cross-coupling reactions of halogenated aryl triflates. This thesis aims to explore new palladium catalyst systems and the conditions of realizing the cross-coupling reactions through these two pathways. To begin with, a brief introduction (Chapter 1) is organized in the following manner. The first part is the development of palladium-catalyzed cross-coupling reactions through C-O bond activation, including the Buchwald-Hartwig amination for C-N bond construction and the application of enol electrophiles in C-C bond formation. The discussion is focused on the reaction of aryl phosphates and enol carboxylates/carbamates. The second part is the development of the palladium-catalyzed chemoselective cross-coupling reactions with the emphasis on the selective activation between Ar-Cl and Ar-OTf bonds. Our study on palladium-catalyzed cross-coupling reactions using O-based electrophiles and halogenated aryl triflates is described in the following parts of this thesis (Chapter 2-6). The exploration of Pd-catalyzed cross-coupling via C-O bond activation began with the employment of triaryl phosphates as electrophiles. On the basis of extensive screening of ligands, Pd/Mor-DalPhos catalyzed system was found to achieve the N-arylation of amines. The reaction conditions exhibited good functional group tolerance and good reactivity toward a wide range of aryl, alkyl amines as well as heterocycles. Solvent-free conditions were applicable with this catalytic system. The gram-scale reaction was also demonstrated. Enol carbamates were selected as O-based electrophiles to construct alkenes due to their atom economy and stability. N-Heterocyclic carbenes were effective ligands to promote Pd-catalyzed cross-coupling reaction between enol carbamates and aryl Grignard reagents. Highly sterically hindered synthesis has been highlighted, and the scope was further extended to alkylation and alkenylation. To examine the practicability, a synthetic route using this cross-coupling reaction was carried out to obtain Tamoxifen and (E)-Tamoxifen. A modular synthetic strategy was adopted in preparing phosphine ligands. The strategy was based on the structural properties of pyrazole derivatives and it was applied in the synthesis of a class of novel phenylpyrazole phosphine ligands. These ligands were tested in palladium-catalyzed cross-coupling of alkenyl pivalates with organomagnesium reagents. PP-Phos showed excellent efficiency as an ancillary ligand in this transformation. The structure investigation showed that both N-iPr and PCy2 are important to the effectiveness of the ligand. The Kumada coupling reactions of alkenyl pivalates were carried out under mild reaction conditions and accommodated a broad scope of substrates, including activated, non-activated, and sterically hindered alkenyl carboxylates. To further explore ligands with new properties, a series of new 2-alkyl indole-based phosphines were designed and synthesized. SelectPhos and its derivatives were found effective in palladium-catalyzed α-arylation of oxindoles and ketones by using a broad scope of chloroaryl triflates as electrophiles. The modification of the ligand structure led to different chemoselective outcome (reacting at Ar-Cl or Ar-OTf). The steric properties of the ligands were found important in this reaction. Based on this discovery, a synthetic strategy was successfully applied in the synthesis of Flurbiprofen. Based on the Pd/SelectPhos catalytic system, chemoselective C-P bond construction for the modification of poly(pseudo)aryl halides was investigated. H-P(OiPr)2 was an effective phosphorylation reagent to afford aryl phosphonates with broad functional group compatibility. Sequential modification of chloroaryl triflate, based on the chemoselective phosphorylation, was successfully carried out to prepare more complexed organophosphorus compounds. |
| Rights: | All rights reserved |
| Access: | open access |
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