Studies Of Transition-Metal-Catalyzed C-H Bond Functionalization And Decarboxylative Coupling Reactions

Transition-metal-catalyzed coupling reactions have been recognized as an important tool for constructing carbon-carbon and carbon-heteroatom bonds in organic chemistry. During the past decades, traditional coupling reactions such as Heck Reaction, Suzuki-Miyara Reaction, Stille Reaction and Sonogashira Reaction have proved to be powerful in the area of organic synthesis. However, the above mentioned name reactions require prefunctionalization (halogenation or metallation) of the substrate, which restrict the application scope from the standpoint of synthetic efficiency and environmental friendliness. Recently, transition-metal-catalyzed C-H bond functional ization and decarboxylative coupling reactions have been emerged as green and economic alternatives in the formation of carbon-carbon and carbon-heteroatom bonds. Due to the wide distribution and low cost of hydrocarbon compounds and carboxylic acids, transition-metal-catalyzed coupling reactions starting from these two chemical reagents have been receiving intense attention in organic chemistry. This dissertation mainly focused on transition-metal-catalyzed C-H bond functionalization of indolizines and decarboxylative dehydrogenative cross-coupling reactions involving α,β-unsaturated carboxylic acids, which include:1. Palladium-Catalyzed Highly Regioselective Oxidative Coupling Reaction of Indolizines with VinylarenesWe have investigated a Pd-catalyzed dehydrogenative Heck reaction of indolizines with vinylarenes. In the presence of2.2’-bipyridine as ligand and Ag2CO3as oxidant, the reaction delivered a colletion of branched olefination products at C-3position of indolizines. Various C-1substitued indolizines and vinylarenes were employed to extend the scope of this reaction under the optimized reaction conditions and afforded the corresponding products in moderate to good yields. Control experiment indicated that the nitrogen atom in the indozine substrate and the bidentate nitrogen ligand are the main contributor to the success of this branched olefination process with unusual regioselectivity. A plausible reaction mechanism was proposed based on the experimental results and previous work about the regioselectivity of Heck reaction. This reaction represents the first example of branched olefination process starting from carbon-hydrogen bond instead of carbon-halogen bond or carbon-metal bond with complete internal selevtivity of vinylarenes.2. Palladium-Catalyzed Oxidative Reactions of Indolizines and α,β-Unsaturated Carboxylic AcidsWe have investigated a Pd-catalyzed oxidative reaction system of indolizines with α,β-unsaturated carboxylic acids. It was found that through properly tuned reaction conditions, three different kinds of products were obtained. Depending on the choice of oxidants, acylated product at C-3position or annulated product at C-3and C-5positions were obtained in moderate yields. In the absence of base additive, the process would switch from annulation to branched olefination. The whole process involves selective cleavage of C-H bond&C=C double bond, protodecarboxylation and decarboxylative dehydrogenative annulation. The substrate scopes of both acylation and annulation were examined, delivering the expected products in moderate yields. Based on the experimental results and previous reports, a plausible reaction mechanism was proposed accounting for three different kinds of products. The acylation process using potassium chromate as the oxidant provides a novel method for the synthesis of C-3acylated indolizines. The region-defined decarboxylative dehydrogenative annulation from α,β-unsaturated carboxylic acids might be complementary to the traditional annulation of alkynes.3. Copper-Catalyzed Annulation of2-Alkylazaarenes with α,β-Unsaturated Carboxylic AcidsWe have developed an efficient and convenient method for the synthesis of C-2arylated indolizines by copper-catalyzed decarboxylative dehydrogenative annulation of2-alkylazaarenes with α,β-unsaturated carboxylic acids. The substrate scope of this reaction was investigated under the optimized reaction conditions and the corresponding products were obtained in moderate yields. Compared to the previous reports of copper-catalyzed reaction systems involving C-H bond functionalization process, this catalytic system does not require external oxidants. Instead, the reaction released carbon dioxide and hydrogen. Preliminary investigation of the reaction mechanism indicated that in situ generated copper(0) species might be crucial to the success of this reaction. This reaction provides a novel and facile route to C-2arylated indolizines from simple and cheap chemical reagents.4. Copper-Mediated Annulation of Alkyl Ketones with α,β-Unsaturated Carboxylic AcidsWe have developed a copper-mediated decarboxylative dehydrogenative annulation of alkyl ketones with α,β-unsaturated carboxylic acids via oxidative radical process, leading to2,3,5-trisubstituted furans. Through optimization studies, it was found that stoichiomatric amount of copper salts were necessary for achieving the best yield. Different alkyl ketones and α,β-unsaturated carboxylic acids were introduced to extend the scope of the reaction and the corresponding furan products were obtained in moderate to good yields. Control experiment with the addition of free-radical trapping reagent blocked the reaction, indicating that it could be a radical initiation pathway. A plausible reaction mechanism was proposed based on the experimental results and previous reports about radical process of α,β-unsaturated carboxylic acids. This reaction provides a novel method for the synthesis of2,3,5-trisubstituted furans with high efficiency from simple and cheap chemical reagents.