Copper-catalyzed Synthesis Of4-oxopyrimido[1,2-a]indole Derivatives

N-Heterocycles are frequently mentioned in organic chemistry, for theirapplications in the synthesis of natural products, as well as the design of molecules withdifferent pharmaceutical activities. Among these compounds with N-Heterocycles,indole derivatives are particularly important, for its significant roles in synthetic methoddevelopment towards bioactive compounds; while pyrimidinone motif is attracting moreand more attention because of their structure similarity with nucleobases such ascytosine and thymine. Therefore,4-oxopyrimido[1,2-a]indole, the N-fused combinationof indole and pyrimidinone, will draw the attention of chemists. However, furtherresearch is restrained by insufficient synthetic methods.Recently, arylation has been involved to develop synthetic approaches toN-heterocycles. A variety of arylation reactions, including cross-coupling and C-Hactivation, provide convenience for the construction of N-heterocycles. Based upon this,a new, effective and facile method has been designed and investigated for the synthesisof4-oxopyrimido[1,2-a]indole derivatives: two reagents, including readily availableN-(2-halophenyl)-3-oxoalkanamides, and commercially available alkyl2-cyanoacetatesor malononitrile, were used, and the reaction was performed under mild conditions withcheap CuI as the catalyst, pipecolinic acid as the ligand, K2CO3or Cs2CO3as the base,DMSO as the solvent, resulting in moderate to good yields of target products.Mechanism study reveals that it is a domino reaction that undergoescopper-catalyzed C-arylation, intramolecular nucleophilic addition of nitrile by N-H,and intramolecular nucleophilic attack process. The reaction shows good tolerance to avarious of functional groups with different electronic effect and steric hindrance such asalkyl-, aryl-, halo-and trifluoromethyl-groups, while cheaper2-Chloroaniline can beused for the synthesis of N-(2-halophenyl)-3-oxoalkanamides instead of2-Bromoaniline.Furthermore, target products bear activated functional groups such as amino, ester andcyano, throwing lights for further modification of these molecules. After all, thisC-arylation method will be a significant tool for the synthesis of more N-Heterocyclesother than4-oxopyrimido[1,2-a]indole derivatives.