Palladium-catalyzed Double N-arylation Of Primary Amines To Synthesis Phenoxazine And Phenothiazine Derivatives

Phenoxazine and phenothiazine derivatives have been widely used in synthetic study of medical chemistry and biological chemistry due to their anticancer,antitumor,antituberculous,antimicrobial,antioxidant and other biological activity.Their distinctive physicochemical properties make them play an important role in material science,including dye-sensitized solar cells,laser dyes,fluorescent stains,organic light-emitting diodes?OLEDs?and other photoelectric material.Literature methods for the synthesis of phenoxazine and phenothiazine derivatives include intermolecular C-N coupling reaction which using phenoxazine or phenothiazine as substrates and intramolecular palladium catalytic,Cu catalytic or base catalytic synthesis.These methods need to amine source to the substrates,and then by intramolecular mono N-arylation to synthesize phenoxazine and phenothiazine derivatives.Herein,in this paper,a novel synthetic method for the production of phenoxazine and phenothiazine derivatives is proposed,which is that Palladium-catalyzed double N-arylation of primary amines using di-halo compounds as substrates to synthesize phenoxazine and phenothiazine derivatives,This method avoids the amine source prior to the substrates.Through the screening of ligands,catalysts and bases,we found the optimal reaction condition that using 0.2 mmol bis?2-bromophenyl?ether as substrate,1.1 equiv.aniline as amination reagent,toluene as solvent,5 mol% Pd?OAc?₂ catalyst,10 mol% DPEphos ligand,3.0 equiv.NaOtBu as base at 120 °C for 15 h under protection of nitrogen.We discussed the reaction of functional group tolerance and synthesized 20 different phenoxazine derivatives?N-isoquinolinyl substituted phenoxazine was new compounds.?under the optimal reaction condition.When it comes to the synthesis of phenothiazine derivatives,we made a slightly modified reaction conditions about the synthesis of phenoxazine derivatives: using 0.2 mmol bis?2-bromophenyl?sulfide as substrate,1.1 equiv.aniline or benzylamine as amination reagent,toluene as solvent,5 mol% Pd₂?dba?₃ catalyst,10 mol% rac-BINAP ligand,3.0 equiv.NaOtBu as base at 110 °C for 20 h under protection of nitrogen.We obtained 3 different phenothiazine derivatives in these conditions.Furthermore,we also acquired two products about double N,N-arylation of p-phenylenediamine.All of the target products were characterized by 1H NMR,13 C NMR,melting point and HR-MS or LR-MS.Palladium-catalyzed double N-arylation of primary amines provides a new method and thought to the synthesis of phenoxazine and phenothiazine derivatives,which has a certain significance in organic synthetic methodology.