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Title: Transition metal-catalyzed oxidative C-H bond functionalization reactions
Authors: Yuen, On Ying
Degree: Ph.D.
Issue Date: 2016
Abstract: Transition metal-catalyzed C-H bond functionalization for the construction of carbon-carbon and carbon-heteroatom bonds that has numerous applications in pharmaceutical, material, and agricultural chemistry has received much attention in the past decade. It is more straightforward and attractive alternative to traditional cross-coupling reactions with organometallic reagents because of better atom economy, environmental friendliness and more streamlined chemical synthesis. Although significant advances to this field have been reported during the past decade, several challenges remains such as difficulty in activation of inert C-H bond and control of site selectivity. This thesis is to explore transition metal-catalyzed cross-coupling reactions through C-H bond functionalization. In the first half of this dissertation, four studies on palladium-catalyzed functionalization of C-H bonds are explored. Three studies are concerning oxidative reactions between two nucleophiles while another study is regarding traditional protocol utilizing electrophiles and nucleophiles. Firstly, a palladium-catalyzed oxidative Mizoroki-Heck reaction of arylsulfonyl hydrazides with alkenes is developed under atmospheric air as the sole oxidant in an open manner. Using Pd(OAc)₂ (OAc= acetate) and inexpensive, air-stable and moisture-stable phenyl isonicotinate (Chapter 2, L9) as a catalytic system, the efficiency of the reaction can be significantly enhanced. A wide range of arylsulfonyl hydrazides undergo oxidative Mizoroki-Heck reaction with alkenes smoothly. Good to excellent product yields and excellent regio- and steroselectivity are achieved. Functional groups such as halo and ester are well tolerated under this optimized reaction condition. Importantly, this reaction is conducted under atmospheric air in open manner that can reduce heavy metal wastes and lessen the complication of setting reactions' procedures. Secondly, a direct oxidative C-2-arylation of benzoxazoles using arylsulfonyl hydrazides as the aryl sources is described. A simple catalyst system comprising of Pd(OAc)₂ and PPh₃ allows the reactions to proceed smoothly under oxidative reaction conditions. A broad range of arylsulfonyl hydrazides is coupled successfully. Other heteroarenes such as caffeine and benzothiazole are also applicable substrates. Notably, this catalytic system tolerates halogen substituents that offer complement to current cross-coupling reactions which use aryl halides. Thirdly, a general and simple method of copper-mediated direct and regioselective oxidative C3-cyanation of 2,3-unsubstituted indoles using benzyl cyanide as the cyanide anion source is developed. A wide range of indoles undergo cyanation smoothly by employing an inexpensive reaction system of copper(I) iodide under open-to-air vessels. Lastly, the first general examples of direct coupling of heteroaryl chlorides, especially substituted 2-pyridyl chlorides as electrophile in which they were previously found to be problematic, with electron deficient polyfluoroarenes as nucleophiles are reported. Pd(OAc)₂ associated with PCy₂-Phendolephos (Chapter 5, L1) serves as the effective catalyst which allows the challenging direct coupling of heteroaryl chlorides and polyfluoroarenes to be succeeded. In addition to heterocycles, a wide range of non-activated and activated aryl chlorides and alkenyl chloride are iii also applicable under this catalyst system. A variety of functional groups such as aldehyde, keto, ester, nitile and amide is well tolerated. The catalyst loading down to 1 mol% Pd can be achieved.
In the second half of dissertation, two studies with regard to traditional cross-coupling reactions of aryl chlorides with organometallic reagents are carried out. Firstly, palladium-catalyzed Hiyama cross-coupling reaction of aryl and heteroaryl chlorides with aryl and heteroaryltrialkoxysilanes under solvent-free reaction condition is presented. The catalyst system comprising of Pd(OAc)₂ and PCy₂-Andolephos (Chapter 6, L2) is a highly effective for this coupling reaction with low catalyst loading (down to 0.05 mol% Pd) and short reaction time (3 h). A broad substrate scope containing electron-rich, -neutral, and -deficient and sterically hindered aryl chlorides is achieved. Notably, the first general examples of Hiyama cross-coupling reaction using heteroaryltrialkoxysilanes are demonstrated. The presence of acetic acid or water suppresses the decomposition of aryl chlorides and promotes the product yields. A large scale experiment without degasification and purification of reactants is also conducted smoothly. Last but not least, a general palladium-catalyzed borylation of aryl chlorides with pinacol borane is reported. A newly modified indolylphosphine ligand (Chapter 7, L18) is prepared via an efficient protocol involving Fischer indolization from readily available phenylhydrazine and 2'-hydroxyacetophenone. The combination of Pd(dba)₂ and newly modified indolylphosphine ligand (Chapter 7, L18) are shown to be an effective catalyst for the borylation of non-activated and activated aryl chlorides with pinacol borane. Addition of tetra-n-butylammoniumiodide (TBAI) is highly effective for coupling of aryl chlorides bearing function groups such as keto, nitile and ester. 1 mol% Pd catalyst loading can be achieved using this catalytic system.
Subjects: Transition metal catalysts.
Organic compounds -- Synthesis.
Hong Kong Polytechnic University -- Dissertations
Pages: xxv, 563 pages : color illustrations
Appears in Collections:Thesis

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