Methodology Development For Heterocyclic Scaffolds And Versatile C-H Activation Reactions

Heterocyclic scaffolds, especially nitrogen-containing ones, are widespread in modern pharmaceutical drugs. Developing highly efficient synthetic methodologies for a variety of heterocycles will help promote the success of early drug discovery. This dissertation contains the development of synthetic methodologies for three heterocyclic scaffolds, including biologically important 2H-indazoles, 1H-indazoles and pyrazoles. Meanwhile, a novel palladium catalyzed hydroxylation reaction of unactivated aliphatic C(sp3)-H bonds with water was developed, which could be used to synthesize various heterocycles.Compared with literature reported methods, our developed methodologies features novel disconnection o f che mical bonds, catalysis mecha nism, broad substrate scope and valuable applications. For 2H-indazoles, we developed a general and efficient approach for the synthesis of 2H-indazoles through copper(I)-catalyzed intra molecular N–N bond formation under mild conditions. The proposed mechanism mainly involves formed azide-copper(I) complex undergo intramolecular cyclization and aromatization. For 1 H-indazoles, we firstly reported the synthesis of 1 H-indazoles and aza-1H-indazoles by intramolecular aerobic oxidative C-N coupling under transition-metal free conditions. The proposed mechanis m mainly involves molecular oxyge n mediated radical cyclization under high te mperature. For pyrazoles, we firstly reported Ru(II)-catalyzed intramolecular aerobic oxidative C-N coupling reactions for the synthesis of tri- and tetrasubsti tuted pyrazoles. The proposed mec hanis m involves Ru(II)-mediated C-H activation/reductive elimination pathway via Ru-containing six- me mbered cyclic transition state.Transition-metal catalyzed C-H func tionalization reactions have displayed more and more advantages in substrate preparation, late-stage drug modification, unique heterocyclic scaffolds construction and complex molecule retro-synthesis over traditional methods in the past decades. Our newly developed hydroxylation reactions for unactivated aliphatic C(sp3)-H bonds with water by palladium catalysis will promote the synthesis of aliphatic β-hydroxyl carboxylic acids and derivatives and provide novel synthetic routes for heterocycle synthesis.In the past decades, the abuse of antibiotics has result ed in the e mergence and spread of multidrug-resistant bacterial pathogens. There is an urgent need to develop more effective antimicrobial agents to treat infections caused by multi-drug-resistant bacteria. Generally, the above-synthesized compounds have structurally novel and diverse, biologically active heterocyclic scaffolds, which laid the foundation for early novel drug discovery. Initially we envisioned a syste matic phenotypic screening of o ur unique small library might provide hit compounds for devel oping new generation of antimicrobial agents. Fortunately, we successfully identified one parazole-based hit compound, na med HJT-D3. After rational design and syste matic leading compo und optimi zation, we identified one more active compound, na med HJT-D3-60, which displayed bactericidal activities against multidrug-resistant Gram-positive pathogens, including MRSA, VRE and MDRSP.