Ir(Ⅲ)-Catalyzed Intermolecular Amidation Of Unactivated Secondary Csp~3-H Bonds And Cu(Ⅰ)-Catalyzed Reductive Coupling Of Alkenes With Alpha-Imino Esters

Csp3-N bond and Csp3-Csp3 bond belong to the basic chemical bonds which are often encountered in natural products and drug molecules. How to regioselectively construct these bonds has aroused wide concerns to develop various synthetic methods. The strategies involved in functional group-directed Csp3-H amination and the reductive coupling of olefin with carbonyl compounds provide innovative approaches to assembly of Csp3-X bonds(X = C, N, O, and S etal). In this thesis, site-selective intermolecular unactivated secondary Csp3-H amination reaction and the reductive coupling reaction of unactived alkene with alpha-imino esters were described, respectively.Although significant progress has been made in transition metal-catalyzed nitrene inserting into secondary Csp3-H via “outer-sphere mechanism”, the reactive sites are basically limited to active Csp3-H bonds. Besides, some breakthroughs about ligand-assisted intermolecular Csp3-H amination via “inner-sphere mechanism” have been achieved, but these transformations are only limited to primary Csp3-H bonds of alkanes with the ThorpeIngold effect. Therefore, developing a general regioselectively intermolecular amination of unactivated secondary Csp3-H bonds is a challenging task. Herein, we report the first Ir(III)-catalyzed unactivated secondary Csp3-H amination via “inner-sphere mechanism”. Detailed and systematic optimization of this transformation shows that [Ir Cp*Cl2]2(5 mol %)/Ag BF4(20 mol %) reaction system can catalyze intermolecular remote secondary Csp3-H amination reaction between N-alkyl-picolinamide and sulfonyl azide, and construct Csp3-N bond regioselectively in gamma site of alkyl amine. Moreover, this versatile method can allow for secondary even tertiary Csp3-H bond amination of broad linear or branched-chain alkanes from moderate to excellent yields. More importantly, the corresponding control experiment, H/D exchange experiment, the kinetic isotope effect experiment, chiral retained control experiment, Hammett analysis and density functional theory(DFT) calculation have proved that a novel directed metal-nitrene concerted insertion into Csp3-H bond via “outer-sphere mechanism” is involved in the secondary Csp3-H bond amination.During this period that we carried out the Ir(III)-catalyzed intermolecular secondary Csp3-H amination, we also accidentally found a novel metal-free strategy for assembling halogen substituted imidazole [1,2-a]pyridine compounds via imido ortho-position Csp3-H functionalized /cyclization tandem reaction starting from aliphatic carboxylic acids or ketones, 2-aminopyridine as substrates and thionyl chloride as halogen sources. These compounds could be further converted into diverse drugs and bioactive imidazo[1,2-a]pyridines core skeleton.Finally, due to the wide application prospect of non natural chiral alpha- amino acids in biological and pharmaceutical fields, developing efficient method to rapid furnish complex alpha-amino acids has emerged as a major topic of research in organic chemistry. In this reagrds,the reductive coupling reaction of alkene with imines provide a new synthesis strategy for making them. On the basis of our early work about the Ru(II)- catalyzed reductive coupling reactions of conjugate diene with imine compounds, we continue to explore the copper- catalyzed reductive coupling reaction of unactivated alkenes with imine compounds. After screening various copper salt catalysts, reducing agents and additives, it was found that the Cu CN/9-BBN/H2 O reaction system could efficiently catalyze the reductive coupling reaction of unactivated alkenes with imine compounds. Based on the mechanism research results, two plausible reaction path ways were involved in this transformation. The main reaction path is triggered by boron-Cu(I) transmetalation between alkylboron and copper(I) salts with the assistance of H2 O and resulted in the alkylcopper species, then the alkylcopper could undergo migratory insertion or nucleophilic attack on imino carbon to provide target product. More over, nucleophilic addition of alkylboranes to imino C=N bond could also directly give the desired target products. It should be noted that the asymmetric reductive coupling of alkene with imines was also investigated, and the 33% ee of the chiral products was obtained using the chiral 2, 2, 2 ’- isopropylidene bis [(4R)- 4- phenyl- 2-oxazole] copper complexes as catalyst.