Palladium-catalyzed Amination Of Chloro-substituted 5-nitropyrimidines With Amines

Pyrimidine deritivatives are an important class of six-membered heterocyclic compounds,which are commonly contained in drugs and bioactivity compounds.Typical 5-nitropyrimidines are either display biological activies by themselves or can be used as key intermediates of medicinal nucleoside and purine analogues.The traditional synthetic method under aromatic nucleophilic substitution reaction of4,6-dichloro-5-nitropyrimidine and nucleophiles suffers from low selectivity,long reaction time and troublesome operation procedure.So it is necessary to find a more efficient method to synthesize 5-nitropyrimidines.Palladium-catalyzed coupling reaction is widely used in pharmaceutical industry,agriculture and fine chemical industry,and C-N coupling reactions of aryl halides and amines catalyzed by Palladium have become an important tool for aromatic amines.Based on Buchwald-Hartwig cross coupliong reaction,employing 4,6-dichloro-5-nitro-pyrimidine as a starting material,we report a versatile method to synthesis different5-nitropyrimidines.Firstly,we initiated our studies with the screening of the conditions for the coupling of 4,6-dichloro-5-nitropyrimidine and 4-anisidine.Various catalysts,ligands,bases,solvents,molar ratios and temperatures were examined to optimize the reation.The optimized conditions are Pd₂?dba?₃?2 mol%?,R-BINAP?6 mol%?,and K₂CO₃?1.4 equiv?in toluene at room temperature.Secondly,using this optimized reaction conditions,we assessed the scope of the amine coupling partners for the amination of 4,6-dichloro-5-nitro-pyrimidine.For this Pd-catalyzed coupling system,the best yield is generally10%²0%higher than that under original nucleophilic reaction conditions,but the yields varied greatly among different amines.Yields were proved to be greatly dependent on amines'electronic effect and steric crowding when synthesizing mono-substituted products.Thirdly,to further demonstrate the accessibility of this method for C-N coupling reaction,we examined the reaction of 4-amino-6-chloro-5-nitro-pyrimidine with multiple aliphatic,heterocyclic and aromatic amines.This reaction system was proved to be effective for synthesizing amino-substituted pyrimidines.Finally,we turned our attention to amination reactions of di-substituted5-nitropyrimidines.Under the slightly modified reaction conditions,high yields are afforded when various amines work as nucleophiles.All the results prove that this Palladium-Catalyzed reaction system is suitable for mono-substituted pyrimidines as well as di-substituted pyrimidines.