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

• Published in: Angewandte Chemie International Edition Vol. 59; no. 52; pp. 23755 - 23762
• Main Authors: Du, Fei, Li, Shi‐Jun, Jiang, Kun, Zeng, Rong, Pan, Xi‐Chun, Lan, Yu, Chen, Ying‐Chun, Wei, Ye
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 21.12.2020; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkenes; Alkenes - chemistry; Alkylation; Alkynes; Alkynes - chemistry; Biological activity; Cascade chemical reactions; Catalysis; Chemical reactions; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Homeostasis; Inflammation; Iron; Iron - chemistry; iron catalysis; Lipopolysaccharides; Macrophages; Oximes; Oximes - chemistry; Physical Sciences; Pyridines; Pyridines - chemistry; radical relays; Relay; Science & Technology; Substrates; synthetic methods; HIGHLY FUNCTIONALIZED PYRIDINES; DIELS-ALDER REACTIONS; ONE-POT SYNTHESIS; radical relays; 2+2+2 CYCLOADDITION; C-H FUNCTIONALIZATION; oximes; SUBSTITUTED PYRIDINES; O-ACYL OXIMES; pyridines; REGIOSELECTIVE SYNTHESIS; ATOM-TRANSFER; iron catalysis; BOND; synthetic methods
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202010752

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. An efficient iron‐catalyzed radical relay protocol enabled the rapid assembly of a wide array of structurally interesting fused pyridines from alkyne‐tethered oximes and alkenes (see scheme). 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.