Heterogeneous Fe single-atom catalysis for C2–H amidation of pyridine/quinoline N-oxides: streamlined synthesis of pharmaceutical scaffolds

Abstract

We present a novel single-atom catalytic strategy for direct C2–H amidation of pyridine/quinoline N-oxides, employing a nitrogen-doped carbon matrix to stabilize atomic iron sites (Fe–N/C). This heterogeneous system overcomes critical limitations of traditional homogeneous approaches by eliminating stoichiometric bases and additives while achieving 100% atom economy without generating toxic byproducts. The Fe–N/C catalyst exhibits broad functional group tolerance, coupling diverse nitriles (aromatic, aliphatic, and heterocyclic) with various heteroaromatic N-oxides in yields of 61–95%. It demonstrates excellent recyclability and gram-scale applicability. The system's pharmaceutical utility is highlighted through: (i) precise synthesis of immunomodulators imiquimod and resiquimod from inexpensive, readily available quinoline precursors; (ii) a streamlined one-step synthesis of betrixaban intermediates, replacing hazardous two-step processes that generate toxic waste and explosion risks; (iii) efficient preparation of grain-protective cloquintocet-mexyl derivatives. Mechanistic studies indicate that the catalytic efficiency originates from both FeN₄-mediated structural modulation and Fe 3d_z²-substrate orbital interaction, which collectively reduce the activation barrier. This Fe–N/C system establishes a green catalytic paradigm for sustainable pharmaceutical synthesis, enabling environmentally benign late-stage modification of complex drug architectures.