Heterogeneous Single-Site copper in Hierarchical MOF Microspheres Enables Sustainable Urea-Functionalization of Quinoline N-Oxides

Abstract

Ureas are privileged scaffolds across drug discovery and materials science, yet their installation onto complex pharmacophores, such as quinoline derivatives, remains challenging due to the inherent limitations of conventional homogeneous catalysts, including poor recoverability and persistent metal contamination. Here, we develop a novel heterogeneous strategy for C2-H functionalization of sterically demanding quinoline derivatives using a hierarchically porous MOF-253-supported single-site copper catalyst (MOF-253-Cu), where the pore architecture and atomically dispersed Cu²⁺ sites synergistically address mass transport and activation constraints of bulky substrates. The protocol achieves the first heterogeneous urea-functionalization of quinoline N-oxides, with 100% atom economy, high selectivity and advantageous green chemistry metrics (E-factor: 1.55; RME: 39.2%). Under optimized conditions, the catalytic system accommodates diverse quinoline N-oxides and carbodiimides-including pharmacologically relevant substrates such as cloquintocet-mexyl-yielding sterically hindered quinolin-2-yl urea derivatives in 80-95% yields with excellent functional group tolerance. MOF-253-Cu demonstrates robust reusability (89% activity retention over eight cycles) with negligible metal leaching (<0.1 ppm), while its gram-scale applicability validates practical utility. Computational studies reveal that the MOF-253-Cu catalyst operates via a stepwise, Lewis acid-activated mechanism, wherein coordination to the carbodiimide substrate is pivotal for reducing the key cycloaddition barrier, ultimately enabling efficient ureidation of quinoline N-oxide. This work establishes a practical and sustainable platform for precision synthesis of pharmacologically relevant scaffolds, particularly for bulky molecular architectures.