Design,Synthesis And Antifungal Bioactivity Of Novel Oxazolines And Analogues

With extensive and significant biological activity,oxazoline analogues have attracted wide attention from pharmaceutical chemists and pesticide chemists.At the same time,they can be used as ligands in synthetic chemistry to promote various transformations.In recent years,C-H direct functionalizations have achieved with oxazoline as a directing group,leading to the rapid construction of various functional molecules.2-Phenyl-oxazoline analogues are widely distributed in natural products and bioactive molecules.Previous studies have shown that they can be used as potential pharmacophores to construct new molecules with antifiungal activity.In this study,nicotinamide was used as a substrate for highly selective C-H amination and etherification on the pyridine ring mediated or catalyzed by eopper salts.Meanwhile,novel isoxazoline analogues were prepared based on the natural product eugenol and commercially available benzaldehydes.Antifungal activities and structure-activity relationships of these compounds were studied for the discovery of novel antifungal agents.The results obtained are as follows:(1)Regioselective C-H anination mediated by copper salts of nicotinamides was achieved with 2-phenyl-oxazoline as a directing group.The regioselective ortho C-H amination of the pyridine ring can be achieved by the copper nitrate system,,while the regioselective para C-H amination of the pyridine ring can be accomplished by copper iso-octanoate system.,With the optimized conditions,versatile amines can be utilized for the direct amination of pyridine rings.This procedure can also be applied for the functionalization of aromatie acids.This C-H fimctionalization proeedure features mild reaction conditions,easy removal of the guiding group and wide functional groups tolerance.(2)Copper catalyzed regioselective etherification the pyridine ring of nicotinamide with different phenols was established after fine tuning of the aforementioned reaction conditions.It's noteworthy that the stoichiometric amount of copper salts can be reduced to catalytic loading to enable firect etherification.The practical potential of this methodology was demonstrated by the first introduction of C-H direct etherification to the synthesis of diflufenican.To the best of our knowledge,this is the first application of C-H functionalization to the synthesis of agrochemicals.A series of functionalized nicotinic acids can be furnished efficiently through the established C-H functionlization,which can serve as scaffolds for the synthesis of drugs or agrochemicals,and important pharmacophores for the rapid discovery of novel analogues of important bioactive molecules.(3)Based on the natural product eugenol,38 isoxazolines were efficiently prepared through a 1,3-dipolar cycloaddition reaction using cheap and readily available aromatic aldehydes as the starting material,37 of them were new compounds.The structure was determined by LC-ESI-MS and 1H-NMR.The first exploration of these synthesized isoxazolines as agrochemicals was carried out,and bioactvity test showed that the synthesized isoxazolines possessed advantages over the original model.Those compounds demonstrated moderate to good activity against Sclerotinia sclerotiorum,Rhizoctonia solani,Alternaria solani,and Phytophthora capsici.The promising candidate 4az showed good inhitory effect against Sclerotinia selerotiorum with EC50 value of 14.3 mg/L,which can be used as a novel antifungal lead for the futher optimization.In summary,oxazoline was used as a directing group to achieve regioselective C-H amination and etherification,and it was applied for the construction of diflufenican and its isomers.A series of new isoxazolines were rapidly constructed and explored for antifungal potentials based on eugenol.171 compounds were synthesized,of which 168 were reported for the first time.The antifungal structure-activity relationship will lay solid foundation for the discovery of novel chiral fungicides containing oxazoline.