Purine isosteres namely azolo[1,3,5]triazines are actively investigated scaffolds in drug development and there is an ongoing demand for new effective methods for their synthesis. Various drawbacks of existing methods led us to attempt developing a novel multicomponent approach for the efficient synthesis of azolo[1,3,5]triazines. During the optimization stage, multicomponent reaction (MCR) of aminoazoles with trialkyl orthoformate and cyanamide under conventional heating resulted in the formation of complex mixtures with traces of the desired product. However, we found that conducting the reaction under microwave heating resulted in dramatic changes in the outcome with improvements in selectivity of the reaction, yields and product purity. We expanded the substrate scope by applying the MCR to substituted aminoazoles and trialkyl orthoesters in their reaction with cyanamide to diversify the products. The reactions proceeded chemo- and regioselectively affording libraries of difficultly accessible azolo[1,3,5]triazines. The intrinsic characteristics of the developed MCR (atom economy, efficiency, convergence) were proven to be advantageous compared to those of sequential multi-step syntheses. Therefore, our MCR could be a valuable tool in the repertoire of practical synthetic methods for the synthesis of 1,3,5-triazine-based purine isosteres. Operational simplicity, short reaction time and high product purity makes this method attractive for the generation of different azolo[1,3,5]triazine libraries in the drug discovery process.

One-pot, multicomponent synthesis of azolo[1,3,5]triazines via selective 1,3,5-triazine ring annulation onto aminoazoles

2019 Fall National Meeting

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