Iron‐Catalyzed Radical Relay Enabling the Modular Synthesis of Fused Pyridines from Alkyne‐Tethered Oximes and Alkenes

Abstract

We have rationally designed a new class of alkyne‐tethered oximes and applied them in an unprecedented iron‐catalyzed radical relay protocol for the rapid assembly of a wide array of structurally new and interesting fused pyridines. This method shows broad substrate scope and good functional‐group tolerance and enabled the synthesis of several biologically active molecules. Furthermore, the fused pyridines could be diversely functionalized through various simple transformations, such as cyclization, C−H alkylation, and a click reaction. DFT calculation studies indicate that the reactions involve cascade 1,5‐hydrogen atom transfer, 5‐exo‐dig radical addition, and cyclization processes. Moreover, preliminary biological investigations suggest that some of the fused pyridines exhibit good anti‐inflammatory activity by restoring the imbalance of inflammatory homeostasis of macrophages in a lipopolysaccharide‐induced model.

Reactivity of oximes for diverse methodologies and synthetic applications

“…Competing intramolecular C-N bond forming and intermolecular C-C bond forming pathways highlight the challenges associated with harnessing radical 47 (ref. 50 ). Oximes that incorporate tethered γ,δ-alkenes (50) tend to spontaneously cyclize upon iminyl radical (52) formation through a 5-exo-trig cyclization, which results in the formation of an exocyclic primary or secondary C-centred radical (53).…”

“…Vinyl radical 48 reacts with an extraneous alkene to form fused pyridine 49 (ref. 50 ). g, Alkene-containing oxime cyclizes on formation of the iminyl radical (52).…”

“…f, Oxime bearing a pendant alkyne undergoes 5-exo-dig cyclization following 1,5-HAT from the iminyl radical(46). Vinyl radical 48 reacts with an extraneous alkene to form fused pyridine 49 (ref 50. ).…”

Superiority of Iridium Photocatalyst and Role of Quinuclidine in Selective α-C(sp3)–H Alkylation: Theoretical Insights

“…Also, the reported theoretical model is a good means to make up for the experimental difficulties. 29,30 Also, the emerging investigations on the C−H activation on the basis of the photocatalyst in view of theoretical chemistry is helpful. Chen et al considered relativistic effects to analyze the electron-transfer mechanism for the uranyl-catalyzed C−H fluorination.…”

Construction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor

“…Such natural product-like properties, plus their synthetic accessibility, make these compounds more suitable for hit discovery. Pitifully, only a very limited portion of them have been employed in further pharmacological research, although many preliminary evaluations have proved their bioactive potential 15,[17][18][19] . Therefore, the construction of a synthetic methodology-based compound library would be beneficial for systematically studying their pharmaceutical potential 20,21 ; and we assume that the special chemical space of the synthetic products would be particularly suitable for those challenging targets such as protein-protein interactions (PPIs) 22,23 .…”