A Novel Strategy For Green Synthesis Of New Polyheterocyclic-Fused Quinoline-2-Thiones

The development of novel methods of green organic synthesis has become the main theme of modern organic synthesis and significant targets of organic chemists.The basic concepts of green chemistry include:avoiding the use of strong acids or bases,unrecoverable metal catalysts and toxic organic solvents in traditional organic synthesis,simplifying tedious reaction operation.Polyheterocyclic compounds exist in a lot of drugs and biologically active molecules,and have very important applications in the fields of pharmacy,materials,agriculture,etc.In fact,nearly 60%of the drugs approved by the US FDA are nitrogen-containing heterocyclic compounds.Therefore,the development of a novel green reaction with atom-and step-economy has essential practical significance and potentially applicable prospects.Quinoline-2-thione is a privileged structural motif which is widely found in a large array of biologically active products and synthetic pharmaceuticals with remarkable pharmacological properties.Three traditional methods for the synthesis of quinoline-2-thiones are shown in the figure above.These methods often require expensive and toxic metal catalysts,or the presence of strong acids(TfOH),bases(DBU),unrecoverable organic solvents.Many of these reactions also need a long reaction period.Therefore,the development of novel,green and convenient process for synthesis of quinoline-2-thiones or even polyheterocyclic-fused quinoline-2-thiones is highly desirable.In this paper,two efficient and green synthetic strategies for constructing novel polyheterocyclic-fused quinoline-2-thiones in one-pot have been developed:(i)A novel strategy for microwave-assisted synthesis of polyheterocyclic-fused quinoline-2-thiones in water(Path 1):An efficient synthetic strategy for the preparation of polyheterocyclic-fused quinolin-2-thiones in one pot was developed,in which a series of o-heteroaryl anilines and carbon disulfide were used as the reaction substrates via microwave-assisted reaction in H2O at 140? for 30 min,24 target products were synthesized with the highest yield up to 99%.On basis of the control experiments,the mechanism via the 6?-electron cyclization process was proposed(Path 1).By calculating E-factor(0.45)and EcoScale(85.5),it is verified that the synthetic method have merits of green synthesis.Recycle experiments of aqueous media,demonstrated that the water in the reaction can be reused as least five times.(ii)A novel strategy for the synthesis of polyheterocyclic-fused quinoline-2-thiones in the green solvent PEG-200(Path 2):A directly synthetic strategy for the preparation of polyheterocyclic-fused quinolin-2-thiones was developed,by reacting a series of o-heteroaryl anilines with isothiocyanate in the green solvent PEG-200 at 100? for 30 min,27 target products were synthesized with the highest yield up to 90%.Based on a series of control experiments,a 6?-electron cyclization reaction mechanism was proposed(Path 2).The significant advantages of this novel synthesis strategy include:catalyst-,acid-and base-free,green solvent,efficient synthesis in one pot,and facile isolation via simple filtration,etc.