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An acid‐promoted cascade reaction of N‐(4‐chloroquinolin‐3‐yl)carbamates with amines is described. This method achieves the formation of two new C–N bonds through an intermolecular amination/intramolecular cyclization reaction sequence. In combination with a subsequent Suzuki coupling reaction, this three‐component telescopic procedure provides rapid access to various bioactive imidazo[4,5‐c]quinolin‐2‐one derivatives. [ABSTRACT FROM AUTHOR]

The serotonin 5-HT 2 receptors are important pharmaceutical targets involved in signaling pathways underlying various neurological, psychiatric, and cardiac functions and dysfunctions. As such, numerous ligands for the investigation of these receptors' activity and downstream effects have been developed synthetically or discovered in nature. For example, the heteroyohimbine natural product alstonine exhibits antispychotic activity mediated by 5-HT 2A/2C agonism. In this work, we identified a heteroyohimbine metabolite containing a serotonin pharmacophore and truncated the scaffold, leading to the discovery of potent agonist activity of substituted tetrahydro-β-carbolines across the 5-HT 2 receptor family. Extensive SAR development resulted in compound 106 with EC 50 values of 1.7, 0.58, and 0.50 nM at 5-HT 2A , 5-HT 2B , and 5-HT 2C , respectively. Docking studies suggest a π-stacking interaction between the tetrahydro-β-carboline core and conserved residue Trp 6.48 as the structural basis for this activity. This work lays a foundation for future investigation of these compounds in neurological and psychiatric disorders., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

An acid-promoted cascade reaction of 4-chloroquinolin-3-yl carbamates with amines is described. This method achieves the formation of two new C-N bonds through an intermolecular amination/intramolecular cyclization reaction sequence. In combination with subsequent Suzuki coupling, this three-component telescopic procedure provides rapid access to various bioactive imidazo[4,5- c ]quinolin-2-one derivatives.