Work

Synthesis of 1,3-Dihydro-2,1-benzisoxazoles by Intramolecular C–N Coupling: Evaluation as an Indane Bioisostere

Year: 2026

Type: article

Abstract: Despite the ever-increasing interest in isoxazole-based compounds, benzo-fused isoxazolidines, or 1,3-dihydro-2,1-benzisoxazoles, are very rare. Seeking to fill this gap, we present a method for the synthesis of 1,3-dihydro-2,1-benzisoxazoles by intramolecular Cu-mediated or Pd-catalyzed C-N coupling of bromoaryl benzylic hydroxylamine derivatives, which can be further derivatized through a simple reductive amination sequence. This approach overcomes the limitations of previous methods and provides access to multiple novel heterocyclic scaffolds. As a proof of concept, we apply the method to the synthesis of a benzisoxazoline analogue of the metabolically labile chiral indane-based MT1/MT2 receptor agonist ramelteon, ultimately furnishing a compound with a >10-fold improvement in metabolic stability in human hepatocytes. Support for the bioisosteric nature of the 1,3-dihydro-2,1-benzisoxazole and indane cores was provided in the context of the ramelteon analogue by DFT calculations.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.6c00429

Authors: Thomas D. Beckler, David Crich

Institution: University of Georgia

Language: English

Topic: Catalytic C–H Functionalization Methods

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: Pharmaron, University of North Carolina at Chapel Hill, National Institute of Mental Health