|Author:||Choy, Pui Ying|
|Title:||Palladium-catalyzed functionalization of C(sp)-H and C(sp2)-H bonds|
Hong Kong Polytechnic University -- Dissertations
|Pages:||xxiii, 512 pages : illustrations ; 30 cm|
|Abstract:||Functionalization of unreactive arene C-H bonds has recently received intensive attention. Mild and selective methods for the direct transformation of carbon-hydrogen bonds to carbon-oxygen/ carbon bonds are undoubtedly found widespread applications across the field of pharmaceuticals, agrochemicals, natural products and feedstock commodity chemicals. However, the C-H bond functionalization remains a critical challenge in organic chemistry. The foremost difficulty lies to achieve high levels of regioselectivity, chemoselectivity and the activation of inert nature of C-H bonds. One of the strategies to achieve the goal is transition metal-catalyzed C-H bond functionalization. In the first half of this dissertation, we explore four studies on the palladium-catalyzed functionalization of C(sp)-H and C(sp2)-H bonds. Firstly, a general and simple method of palladium-catalyzed direct and selective oxidative C3-acetoxylation of 2,3-unsubstituted indoles has been developed. The first examples of selective carbon-hydrogen bond cleavage followed by carbon-oxygen bond formation sequence is achievable without any ortho-directing groups. This protocol requires 2 mol% Pd-loading under mild reaction conditions (70 °C and with weak base, KOAc) which tolerates a variety of functional groups. It is compatible to bromo-group which is a useful component for potential chemical transformations using coupling technology. Secondly, a palladium-catalyzed C-H bond oxygenation reaction of aromatic ketones is presented. This first example of carbon-hydrogen bond functionalization followed by carbon-oxygen bond formation sequence has been accomplished with ketone moiety as the ortho-directing group. This protocol provides a facile access to a wide range of ortho-acylphenol compounds from arylketones. Next, the first general palladium-catalyzed direct arylation of polyfluoroarenes with aryl sulfonates is described. This coupling protocol performs under relatively mild reaction conditions (90 °C with weak base, KOAc and without addition of acid additives) for successful coupling with both aryl tosylates and more challenging aryl mesylates. Last, the palladium-catalyzed Sonogashira coupling of aryl/ heteroaryl sulfonates is explored. A variety of functional groups are compatible such as nitrile, aldehyde, keto, and amide. This versatile coupling approach provides a facile access to 2-substituted isoquinoline by a one-pot cascade process.|
In the second half of this dissertation, we engineer the syntheses for new family of monodentate phosphine ligands. The straightforward syntheses involve facile, high yielding conversion of Fischer Indolization into a broad scope of potentially and differentially substituted phosphine ligands. Besides, a modification of well-developed CM-phos with altering the N-substituted group is carried out. By expanding the size of the protecting group, both the steric and electronic properties of ligands are tuned. Furthermore, inspired by previously developed Andole-phos and Nadole-phos, a new family of ligands is designed with combined electronic (OR) and steric effect (naphthyl). The newly modified CM-phos-Ni-Pr uncovered a facile approach for challenging tri-ortho-substituted biaryl synthesis with carbon-carbon bond formation. To our delights, it represents the first palladium-catalyzed Suzuki-Miyaura cross-coupling of sterically demanding aryl arenesulfonates that proceeded smoothly at low catalyst loading (0.2-1.5 mol% Pd) within 24 h to generate good to excellent product yields.
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