N-O As Directing Group For The C-H Bonds Functionalization

C-H bond activation has recently attracted great attention owing to its advantages of environmental friendly and atom economy, which has been widely applied to the syntheses of natural products, drug molecules, and functional materials. In addition, the high reactivity and good regioselectivity of N-oxide compounds make them become the hot topic in organic synthesis using N-oxide as a directing group. Therefore, in recent years, we focused on the functionalization of N-oxide compounds based on C-H bond activation.In this thesis, the synthesis of biheteroaryls under metal-free conditions and direct C-H bonds acylation of N-oxide compounds are studied. The main results obtained are shown as bellows: 1. Double C-H bond activation of quinoline N-oxides with 1,3-azoles under metal-free conditions.Biheteroaryl is an important buiding block, applied widely in organic synthesis, advanced functional materials, and pharmaceuticals. Conventional methods to build such structures typically involve multistep cryogenic reactions and transition-metal-catalyzed coupling reactions. However, some problems still exist with these procedures, such as the harsh reaction conditions, and usage of noble metals. Therefore, a direct cross-coupling of quinoline N-oxides with 1,3-azoles via double C-H bonds activation under metal-free conditions has been realized using tBu OLi as a base, xylene or DMF as solvents. And this new methodology had been demonstrated to be suitable for the cross-coupling of quinoline N-oxides with 1,3-azoles with a broad range of substrates, which afforded a broad range of biheteroaryls in up to 95% yields(Scheme 1). This one-pot method has the advantages of easy operation, mild conditions, and avoiding the use of precious metals, oxidants, additives. This strategy was designed from atom-economic, green chemisty and sustainable development points of view. 2. “One pot” approach to 8-acylated 2-quinolinones via Pd-catalyzed regioselective acylation of quinoline N-oxidesRecently, a number of catalytic procedures have been reported for the C-H activation of quinoline N-oxides, most of them allow functionalization at the C-2 position. However, the procedure to C8-substituted quinolines is rarely reported. On the other hand, 2-quinolinone is a naturally occurring class of compounds, which exhibit a broad spectrum of pharmacological activity. Therefore, a novel and convenient protocol to the 8-acylated 2-quinolinones in moderate to high yield has been developed from quinoline N-oxides and benzaldehydes using palladium chloride as the catalyst, TBHP as the oxidant, water as the additive and DCE as the solvent(Scheme 2). This method is the first time using the one-pot tandem method to synthesize C8 activation of 2-quinolinones with quinoline N-oxides, which obtained the high selectivity of products and a broad range of substrates. Mechanistic studies indicate that water played an important role as a source of oxygen atom in the reaction and a palladacycle intermediate has been isolated from the catalytic conditions. This method is simple and efficient, and provides a meaningful way to obtain quinolinones with pharmacological activity. 3. Palladium-catalyzed C8-selective C-H acylation of quinoline N-oxidesTransition metal catalyzed direct C-H bond functionalization has emerged as an ideal strategy in organic transformations. The challenge still remains with the regioselective C-H bond functionalization since multiple C-H bonds are present in most organic molecules. Therefore, N-oxide has been intensively investigated, which has been used to achieve the desired regioselective control. A number of catalytic procedures have been reported for the C-H activation of quinoline N-oxides, most of them allow functionalization at the C-2 position. However, the procedure to C8-substituted quinolines is rarely reported. Herein, a simple and efficient protocol to C8 regioselective acylation of quinoline N-oxides has been developed. A series of C8 activated quinoline N-oxides arylketones were obtained using palladium chloride as the catalyst, ɑ-oxocarboxylic acids as the acylation reagent and K2S2O8 as the oxidant(Scheme 3). Mechanistic studies indicate that a palladacycle intermediate has been isolated from the catalytic conditions. This method is simple and efficient and provides a meaningful way to selective activated quinoline N-oxides. 4. Direct access to ortho-acylation of azoxybenzenes via Pd-catalyzed C-H regioselective functionalization using alcohols as acyl sourcesAromatic azo compounds have been extensively investigated in analytical chemistry, functional material, medicine, organic synthesis and industrial dye for their photochromic properties. The challenge still remains with the regioselective C-H bond functionalization of azobenzenes because of the low regioselectivity of azobenzenes. Herein, a simple and efficient protocol to high regioselective ortho-acylation of azoxybenzenes has been developed. A series of ortho-acylatied azoxybenzenes arylketones were obtained using palladium acetate as the catalyst, alcohols as the acylation reagent and TBHP as the oxidant(Scheme 4). In this system, different substituents of the substrates can be successfully participated in the reaction, which has good substrate universality. In addition, a palladacycle intermediate had been isolated from the catalytic conditions, which confirmed the feasibility of this mechanism and laid a foundation for this type of reaction later.