Organocatalytic Asymmetric C-H Vinylation Of N-Acyl Heterocycles

N-heterocycles structures are key units in numerous bioactive molecules and have been used for many pharmaceutical applications. Especially some substituted tetrahydroisoquinolines, piperidines and indolopiperidine tetrahydro-β-carbolines as potential therapeutic agents for treatment of diverse diseases has shown an incredible increase. The catalytic enantioselective addition to synthesize these structural motifs have garnered intensive attention. Recently, the direct enantioselective C-H functionalization emerged as an attractive alternative without prior installation of functional groups. Employing the aryl moiety as the activating and protecting group for tetrahydroisoquinolines proves to be a problem because the aryl group is not easily cleaved. So, we hope to report the first organocatalytic enantioselective oxidative C-H functionalization of N-acyl substrate. With respect to the synthesis of a-substituted tetrahydro-β-carbolines, aside from the enantioselective hydrogenation of cyclic imines, the organocatalytic asymmetric Pictet-Spengler reaction has recently emerged as an elegant approach providing the scaffolds with excellent enantioselectivity. Organocatalytic enantioselective C-H functionalization reactions of N-carbamoyl tetrahydro-β-carbolines have never been described. Substituted pyridinium ions have been shown to be ideal intermediates for piperidine synthesis, Organocatalytic enantioselective C-H functionalization reactions of N-carbamoyl piperidines have never been described. So, we hope to report the organocatalytic enantioselective oxidative C-H functionalization of N-acyl substrate.In the second chapter, The first organocatalytic enantioselective oxidative C-H functionalization of N-acyl tetrahydroisoquinolines with vinyl boronates promoted by a chiral Bronsted acid is described. We describe the organocatalytic enantioselective C-H functionalization of N-acyl tetrahydroisoquinolines with a variety of vinyl boronates. A broad range of structurally and electronically diverse tetrahydroisoquinolines were well tolerated with this metal-free process. The N-carbamoyl protecting group can be easily cleaved under mild conditions, affording corresponding enantiopure secondary amines in high efficiency. Control experiments were performed to explore the roles of the solvent and addtive.Then in the third chapter, The first organocatalytic enantioselective C-H vinylation reactions of N-carbamoyl tetrahydro-β-carbolines is described. We have developed the organocatalytic enantioselective oxidative C-H vinylation of N-carbamoyl tetrahydro-β-carbolines with a wide range of boronates. With respect to the synthesis of a-substituted tetrahydro-β-carbolines, aside from the enantioselective hydrogenation of cyclic imines, the organocatalytic asymmetric Pictet-Spengler reaction has recently emerged as an elegant approach providing the scaffolds with excellent enantioselectivity. However, this transformation requires the involvement of electron-rich tryptamines, leaving electron-deficient THCs inaccessible. Moreover, enals also cannot be employed as substrates, rendering a-vinyl-substituted tetrahydro-β-carbolines unavailable. Mechanistic studies indicated the intermediacy of a reactive dioxaborolane and elucidated the roles of the CF3CH2OH additive in the C-H oxidation and nucleophilic addition processes.In the forth chapter, The first organocatalytic enantioselective C-H vinylation reactions of N-carbamoyl tetrahydropyridines is described. The metal-free processes represent an efficient and straightforward approach to a variety of structurally and electronically diverse a-substituted tetrahydropyridines in good yields with excellent regio-and enantioselectivities. And a broad range of electronically diverse vinyl boronates were well tolerated. The influence of the substituents on the tetrahydropyridine scaffold was next studied. Electronically varied 4-aryl-and 4-heteroaryl-substituted tetrahydropyridines were effective substrates, affording the excellent ee values. At the C4 position, alkynyl moieties were also tolerated, and the corresponding products were obtained with high enantiocontrol, demonstrating the capability of the method to prepare structurally diverse 2,4-substituted piperidines through manipulation of the alkyne moieties.In conclusion, the first organocatalytic asymmetric C-H functionalization of N-carbamoyl tetrahydroisoquinolines, tetrahydropyridines and tetrahydro-β-carb-oli-nes with a variety of vinyl boronates has been developed. A broad range of structurally and electronically diverse tetrahydroisoquinolines, tetrahydropyridines and tetrahydro-β-carbolines were well tolerated with this process. The N-carbamoyl protecting group can be easily cleaved under mild conditions, affording corresponding enantiopure secondary amines in high efficiency. Mechanistic studies indicated the intermediacy of a reactive dioxaborolane and elucidated the roles of the CF3CH2OH additive in the C-H oxidation and nucleophilic addition processes.