Synthesis And Antifungal Activity Of Benzoxazine (Azole) Diazepine And Oxazolidone Substituted Benzoxazines

Heterocyclic compounds have been often found as the key structural motifs of pharmaceutical and agricultural chemicals.Pictet-Spengler reaction plays a very important role in the construction of N-heterocyclic system.In this paper,9-aryl-1,4-benzoxazinodiazones III,Benzoxazolone diazepine VI and Oxazolidone substituted benzoxazines VII were designed and synthesized.The structures of the target compounds were characterized by IR,~1H NMR,¹³C NMR and HRMS,and the single crystal structures of some compounds were determined.The antifungal activity of the synthesized compounds was studied.(1)Using 3,4-dihydro-1,4-benzoxazine and 1,2-dibromoethane in Na H as base and anhydrous DMF as solvent to synthesize N-(2-bromo ethyl)-1,4-benzoxazine compound I.Then compound I was reacted with a series of aromatic amines to obtain N-(substituted arylaminoethyl)-1,4-benzoxazine II-1?II-20 with the yield of 43%?72%.(2)The target compounds 9-aryl-1,4-benzoxazinodiazepine?-1??-18 were synthesized by Pictet Spengler reaction of N-(2-arylaminoethyl)-1,4-benzoxazine II with ethyl glyoxylate using La(OTf)₃ as catalyst and toluene as solvent.The yeilds were 40%?68%.(3)N-(2-Bromoethyl)benzoxazolone IV was synthesized with the yield of 80%by the reaction of benzoxazolinone with excess 1,2-dibromoethane in the presence of Cs₂CO₃ and TBAI as phase transfer catalyst at 80?for 1 h.Then compounds IV react with a series of aromatic amines to obtain N-(substituted arylaminoethyl)benzoxazolone?-1??-23.The conditions were as follows:n(I):n(aromatic amine):n(Na I):n(K₂CO₃)=1:1.1:1.1:2,reaction temperature was 90?,acetonitrile was used as solvent,reaction time was 24 h,the yields were40%?58%.(4)Using N-(substituted arylaminoethyl)benzoxazolone V reacted with ethyl glyoxylate at 95?in La(OTf)₃ as catalyst and toluene as solvent to synthesize Benzoxazolone diazepine VI-1?VI-4 and Oxazolidone substituted benzoxazines VII-1?VII-7.When the benzene ring of V had a substituent at the para position,the reaction had a certain chemical selectivity,and no oxazolone diazepine compound VI was formed,and it was Oxazolidone substituted benzoxazines VII.The yields of compounds VI and VII are both shown as the yield of electron-donating groups attached to the benzene ring is greater than the yield of electron-withdrawing groups.The reaction conditions were as follows:the mass ratio of compound V to ethyl glyoxylate was 1:2.0,the catalyst was La(OTf)₃(10%mol),toluene was used as the solvent,and the reaction was carried out at 95?for 9 h.(5)The antifungal activity of synthesized compounds II,III,?,VI and?were tested by in vitro method.Among all tested pathogens,the compounds had the best inhibitory activity against S.sclerotiorum.Compounds?-11,?-12,and?-17 showed 88.7%inhibitory activity against S.sclerotiorum,and compound?-18 showed 82.1%inhibitory activity against S.sclerotiorum;The inhibitory activity of compounds?-4,?-6 and?-9 against S.sclerotiorum was the highest,reaching more than 90%;The inhibitory activity of compounds V-13 and VI-1 against S.sclerotiorum were 87.8%and 87.4%,which were higher than Chlorothalonil.