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

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.

Concerted Nucleophilic Aromatic Substitution Reactions

“…Prior to this most recent work, Clayden et al had studied extensive alternative applications of these aryl transfer reactions,notably in ring-expansion reactions, [78][79][80][81][82][83] for example,with substrates 240, 241. [78] Although Hammett plots are not reported for these series,t he analogy to the amino acid cases just discussed make it highly likely that they follow cS N Ar pathways through transition states 244.Inthe presence of dimethylpropyleneurea (DMPU) and lithium diisopropylamide (LDA), ring-expanding isomerisation was effected with excellent retention of stereochemistry.Thus,the initially generated benzyllithium is configurationally stable for the period needed to carry out the rearrangement.…”

Mechanisms and Beyond: Elucidation of Fluxional Dynamics by Exchange NMR Spectroscopy

“…For 187 a , hindered rotation is hypothesized to be related to the bulk of its β‐methyl group ( k rotation =2.2–13 s −1 ), whereas slow rotation of 187 b is likely related to its strong binding within the host ( k rotation =1.0–5.5 s −1 ). Clayden and colleagues used a modified Smiles rearrangement to form luxional medium‐sized rings with a chiral ground state. Their dynamics showed a combination of bond rotation, ring flip (section 3), stereomutation (section 4) and hydrogen‐bond dynamics (section 5).…”

Konzertierte nukleophile aromatische Substitutionen

“…In diesen Fällen übernimmt der Schritt der Enolatbildung diese Rolle. Dieser jüngsten Arbeit vorangehend haben Clayden et al umfangreiche alternative Anwendungen dieser Aryltransferreaktionen untersucht, insbesondere bei Ringexpansionsreaktionen,[78][79][80][81][82][83] z. B. mit den Substraten 240 und 241 [78].…”