Benzo[b]furans/Pyridines Synthesis Via One-pot Nickel/Nitrogen Catalysis And Antibacterial Activity Characterization

Benzo[b]furan/pyridine derivatives are widely present in natural products and usually have a variety of good biological activities.However,the extraction and separation of such compounds in natural products are difficult and with low yield,which has largely hindered their applications in biological activities.At present,the synthesis of benzo[b]furan/pyridine compounds skeletons usually uses expensive and rare metal catalysts such as palladium,rhodium.In this thesis,environmentally and friendly,inexpensive and readily available nickel metal was used as a catalyst,under Cu-free and phosphine-free condition,nickel-catalyzed one-pot method has achieved the Sonogashira coupling cyclization reaction of o-halophenol and arylacetylene to synthesize 2-substituted benzo[b]furans/pyridines.The antibacterial performance of the synthesized 2-substituted benzo[b]furan/pyridine compounds was determined by the mycelium growth inhibition method.With a view to exploring its structure-activity relationship,it lays a theoretical foundation for the application of these compounds.The main achievements are as follows:(1)Using 5-bromo-2,2'-bipyridine with a certain flexibility skeleton as a ligand,nickel catalyzed the one-pot synthesis of 2-substituted benzo[b]furan/pyridine compounds.The reaction system was screened including nickel catalyst,alkali,flexible ligand,different solvents and temperature.Based on this,the tolerance of different functional groups was studied.3-ethynylpyridine and o-iodophenol can obtain 70%of the target product.The introduction of tetrabutylammonium iodide as an additive can improve the reactivity of bromide.(2)Using the rigid skeleton 5-nitro-1,10-phenanthroline as a ligand to achieve nickel-catalyzed synthesis of 2-substituted benzo[b]furan/pyridine compounds.After optimizing nickel catalyst,rigid ligand,alkali,solvent and temperature,the universality of the substrate of nickel catalyst system was explored.3-ethynylpyridine and the large sterically hindered substance 4-tert-butyl-2-iodophenol gave 89%product,the reaction of less reactive 2-bromo-3-hydroxy-pyridine with phenylacetylene yielded a 61%yield,which is better than the catalytic system involving 5-bromo-2,2'-bipyridine.(3)In vitro biological activity of 25 benzo[b]furan/pyridine compounds against four pathogenic bacteria,Alternaria solani,Fusarium oxysporum,Botrytis cinerea,and Alternaria alternate was determined by mycelial growth inhibition method.It was found that the structure of benzo[b]furan/pyridine compounds containing N atoms is beneficial to improve the antibacterial activity against four pathogenic fungi.The virulence test results showed that compound 431 had the highest virulence to Alternaria solani and Fusarium oxysporum,with EC50 of 28.88 ?g/mL and 38.80 ?g/mL,respectively;43m has the best virulence against Botrytis cinerea and Alternaria alternata,EC50 of 31.15 ?g/mL and 23.52 ?g/mL.The relationship between the antibacterial activity and the structure of the compound reveals that the introduction of pyridyl group at the 2-position of benzo[b]furan can effectively improve the antibacterial activity of the compounds against four pathogenic fungi.The introduction of-F at the 5-position reflects Good broad-spectrum,when the concentration was reduced to 40 ?g/mL,the antibacterial rate of the four pathogenic fungi reached more than 70%in 96 hours.In summary,this paper proposes two simple,low-cost,wide-range routes to synthesize 2-substituted benzo[b]furan/pyridine compounds.The results show that the rigid ligand is favorable for the synthesis of o-halophenol and aryl-terminal alkyne.2-Substituted benzo[b]furan/pyridine compounds show good antibacterial activity against four pathogenic fungi.This provides a theoretical basis for the development of new lead compounds with antibacterial and antifungal properties.