Metal-free cascade SNAr reaction/allylic amination enabled by triethylamine: a green chemistry approach to access tetrahydropteridines

Abstract

Herein, we report a novel metal-free cascade S_NAr reaction/allylic amination strategy toward pyrimidinamine derivatives promoted by cost-effective triethylamine, enabling the efficient synthesis of a wide range of 2-chlorotetrahydropteridines in moderate to good yields under an 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 demonstrated through solvent-free optimization, feasibility for gram-scale production, and synthetic application of the resulting products. This green synthetic approach significantly reduces environmental impact by eliminating the need for an inert atmosphere, establishing a robust platform for the sustainable synthesis of tetrahydropteridines.