Medium-Sized-Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion

Romain Costil, Quentin Lefebvre, Jonathan Clayden*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

24 Citations (Scopus)
261 Downloads (Pure)

Abstract

Analogues of dibenzodiazepines, in which the seven-membered nitrogen heterocycle is replaced by a 9-12-membered ring, were made by an unactivated Smiles rearrangement of five- to eight-membered heterocyclic anthranilamides. The conformational preference of the tertiary amide in the starting material leads to intramolecular migration of a range of aryl rings, even those lacking electron-withdrawing activating groups, and provides a method for n→n+4 ring expansion. The medium-ring products adopt a chiral ground state with an intramolecular, transannular hydrogen bond. The rate of interconversion of their enantiomeric conformers depends on solvent polarity. Ring size and adjacent steric hindrance modulate this hidden hydrophilicity, thus making this scaffold a good candidate for drug development.

Original languageEnglish
Pages (from-to)14602-14606
JournalAngewandte Chemie - International Edition
Volume56
Issue number46
Early online date16 Oct 2017
DOIs
Publication statusE-pub ahead of print - 16 Oct 2017

Keywords

  • Cyclization
  • Heterocycles
  • Hydrogen bonds
  • Medium-ring compounds
  • Rearrangements

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