Herein, we report a novel metal-free cascade SNAr reaction/allylic amination strategy for pyrimidinamine derivatives promoted by cost-effective triethylamine, enabling the efficient synthesis of a wide range of 2-chlorotetrahydropteridines in moderate to good yields under air atmosphere. This operationally simple protocol demonstrates notable advantages including one-pot synthesis and utilization of environmentally benign solvents. The obtained 2-chlorotetrahydropteridines serve as versatile synthons for constructing diverse 2-substituted tetrahydropteridine derivatives through conventional palladium-catalyzed Suzuki–coupling and Buchwald–Hartwig amination reactions using (SIPr)Ph₂Pd(cin)Cl as the N-heterocyclic carbene-palladium catalyst. Systematic mechanistic investigations, including successful isolation and monitoring of key intermediates, provide a deeper insight into the reaction pathway. The methodology's sustainability is further evidenced by successful attempts at solvent-free optimization, gram-scale production feasibility, and synthetic application of the resulting products. This green synthetic approach significantly reduces the environmental impact through eliminating the requirement for an inert atmosphere, establishing a robust platform for the sustainable synthesis of tetrahydropteridines.

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