Controllable Synthesis Of Nitrogen-containing Heterocycles Via Cyclization Of Alkynes

Nitrogen-containing heterocycles are widely existed in natural products,pharmaceuticals and materials,thus developing highly efficient synthetic methods to construct these structures is of significant importance.Traditional methods for synthesizing these cycles usually require harsh conditions,such as high temperature,strong acids and strong bases.Transition metal-catalyzed cyclization of alkynes has attracted numerous attention from organic chemists,owing to its mild reaction conditions and facile construction of complex molecules from readily accessible starting materials.Despite these advantages,there are still great challenges for controlling the regio-and chemoselectivity during the reaction process,typically resulting in limited substrate scope and mixtures of two or more isomers,which apparently decreases the reaction efficiency.Hence,developing a controllable method for fine-tuning the selectivity of reactions is urgently required.In this regard,this dissertation focuses on developing synthetic methods for controllable and divergent synthesis of nitrogen-containing heterocycles from cyclization of alkynes,which could be accomplished by finely tuning the ligand effect to control the regio-and chemoselectivity of reactions.(1)Ligand-Controlled Selectively Intramolecular Hydroarylation of Alkynes to Synthesize DihydroquinolinesGold-catalyzed intramolecular hydroarylation of alkyne reactions are powerful methods for constructing dihydroquinolines.However,regioselectivity of substituted aromatics and cyclization of electron-deficient substrates still remains stubborn challenges.Following the understanding of ligand effect of gold catalyst and combined with directing concept in C-H activation,regioselective synthesis of 5-and 7-substituted dihyroquinolines has been successfully achieved.Electrophilic gold complexes,tuned by the electron-deficient phosphite ligand,will deliver corresponding 5-substituted dihydroquinolines.Alternatively,the bulky and electron-rich Xphos ligand supplements steric hinderance and electronic properties,which affords 7-substituted dihydroquinolines.Furthermore,sterically unbiased substrates,like Fluoro-and methyl-substituted one,are well tolerated and provide corresponding products.(2)Selective Cyclization of o-Alkynylbenzamides to Synthesize Isoindolinones and IsoquinolinonesRetrosynthetic analysis demonstrates that isoindolinones and isoquinolinones could be constructed simutaneously via selective cyclization of o-alkynyl-benzamides.Amides behave as peculiar ones compared to other nucleophiles,due to their ambident form resulting in two different nucleophilic sites which diversify the reaction processes and simultaneously enhance the difficulty of controlling the selectivities.For chemoselectivity,we envisaged different “soft” and “hard” transition metals possess distinct coordinations and ambident forms toward different heteroatoms,which could bring chance to differentiate nucleophilic sites.Inspired by the ligand effect in gold catalysis,we anticipated that ligands containing various electronic and steric properties might bring about different regioselectivity of alkynes.(3)Ligand-Controlled Selecive Carbonylation of Alkynes to Synthesize Indolo[3,2-c]coumarins and Benzofuro[3,2-c]quinolinonesIndolo[3,2-c]coumarins and benzofuro[3,2-c]quinolinones,both containing polyheterocycles and retrosynthetic analysis shows that these two sccaffolds could be constructed by 2-hydroxy-2'-amino-diphenylethyne and CO.However,the competitive coordination with catalyst as well as competitive cyclization and carbonylation between the amino and hydroxyl group challenge this facile route.Finally,the O-attack/N-carbonylation cyclization leading to benzofuro[3,2-c]quinolinones is achieved by utilization of Pd(II)as the catalyst and electron-deficient 1,10-phenathrolinone as the ligand,while the bulky and electron-rich ligand reverses the reaction and facilitates N-attack/O-carbonylation cyclization generating indolo[3,2-c]coumarins analogues.Furthermore,various similar structures installed with other nucleophiles are applicable for delivering diverse polycycles in one step,which could serve as convenient ways for compound library construction in drug discovery.