Pd Catalyzes The CH Activation Cyclization Reaction To Synthesize 8-azaharasperin A Derivatives

Protosapanin A(PrA)was one of the active ingredients of the traditional Chinese medicine Caesalpinia sappan L.Some researches in clinic and pharmacology have proved that the PrA exhibited excellent inoxidizability,antineoplastic activity,anti-HIV-1 integrase,and immunodepression and so on.Up to now,the reports about PrA derivatives mainly focus on their bioactivity.Pharmacological studies about the PrA have not been studied deeply,because the PrA in Caesalpinia sappan L was little and the extract of PrA was difficult.From the above,it's meaningful to synthesize the PrA and its derivatives and explore their pharmacological studies.By literature investigation,PrA as the lead compound,8-azaPrA was designed by introducing the imino group to replace the methylene in the heterocycle pieces of PrA.8-AzaProtosapanin A(8-azaPrA)is a kind of dibenzoxazinone structural analogues with good biological activity,and 8-azaPrA derivatives can be obtained by modifying the substituent groups on the aryl ring.A route for the synthesis of 8-azaPrA and its derivatives was designed from and aromatic amines as the starting materials.Phenols were iodized to give 2-iodophenols,and aromatic amines gave a-chloro-N-arylacetamides by an acylation with chloracetyl chloride.Then 2-iodophenols and a-chloro-N-arylacetamides gave the key intermediates 2-(2-iodoaryloxy)-N-arylacetamides by an etherification.Finally 2-(2-iodoaryIoxy)-N-arylacetamides offered 8-azaPrA derivatives by Pd-catalyzed intramolecular C-H activation/C-C cyclization.The etherification and intramolecular C-H activation/C-C cyclization as important reaction steps were investigated.Wherein,the optimal conditions of C-H activation/C-C cyclization were 15 mol%Pd(TFA)2 as the catalyst,2 equiv of AgTFA as the oxidant and 2 equiv of K2CO3 as the additive in DMAC at 120 ?.26 target compounds of 8-AzaPrA and its derivatives were obtained by the abovementioned route.The target compounds and the important intermediates were characterized and confirmed by using HRMS,IR,1H NMR,13C NMR,etc.