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Medium‐Sized‐Ring Analogues of Dibenzodiazepines by a Conformationally Induced Smiles Ring Expansion
Author(s) -
Costil Romain,
Lefebvre Quentin,
Clayden Jonathan
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201708991
Subject(s) - intramolecular force , steric effects , chemistry , ring (chemistry) , conformational isomerism , amide , hydrogen bond , stereochemistry , aryl , smiles rearrangement , molecule , organic chemistry , alkyl
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.