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-benzoxazinodiazepineⅢ-1～Ⅲ-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）benzoxazoloneⅤ-1～Ⅴ-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,Ⅴ,VI andⅦwere tested by in vitro method.Among all tested pathogens,the compounds had the best inhibitory activity against S.sclerotiorum.CompoundsⅢ-11,Ⅲ-12,andⅢ-17 showed 88.7%inhibitory activity against S.sclerotiorum,and compoundⅢ-18 showed 82.1%inhibitory activity against S.sclerotiorum;The inhibitory activity of compoundsⅤ-4,Ⅴ-6 andⅤ-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.