Solvent-controlled switch enables aziridination or Beckmann-type amidation of chalcones with MsONH3OTf.
Background
Organic synthesis relies on precise control over reaction pathways to selectively form desired products. Chalcones are versatile intermediates, but achieving selective functionalization, particularly for nitrogen-containing motifs like aziridines and amides, can be challenging. Aziridines are valuable building blocks in medicinal chemistry, while α,β-unsaturated amides are prevalent in natural products and pharmaceuticals. Current methods often require different reagents or complex conditions to access these distinct structures from similar starting materials, highlighting a gap for simplified, switchable synthetic routes.
Study Design
Researchers investigated the reaction of chalcones with MsONH3OTf (a hydroxylammonium salt) under varying solvent conditions. They performed reactions in two distinct solvents: trifluoroethanol (TFE) and tetrahydrofuran (THF). The primary objective was to observe and characterize the products formed in each solvent. Control experiments were conducted to support the solvent-dependent selectivity. Intermediates were detected using HRMS and a bicyclic O-sulfonyl oxime was isolated, providing insight into the reaction mechanism.
Results
In TFE, the reaction exclusively yielded NH-aziridine derivatives via direct aziridination.
Key Findings
- TFE solvent directs chalcone reaction with MsONH3OTf to form NH-aziridine derivatives via direct aziridination.
- THF solvent directs chalcone reaction with MsONH3OTf to form α,β-unsaturated amides via Beckmann rearrangement.
- Solvent-dependent selectivity is supported by control experiments and
HRMSdetection of a hydroxylamine-derived intermediate. - Isolation of a bicyclic O-sulfonyl oxime provides evidence for a trapped intermediate-like species in the Beckmann-type pathway.
Why It Matters
This solvent-controlled strategy offers a highly practical and efficient method for selectively synthesizing two distinct, valuable nitrogen-containing motifs from common chalcone precursors using a single reagent. For synthetic chemists, this provides a powerful tool to precisely direct reaction outcomes, simplifying synthetic routes and potentially accelerating drug discovery efforts. The ability to switch between aziridination and amidation by merely changing the solvent represents a significant advance in atom-economical and selective synthesis, reducing the need for multiple reagents or complex protecting group strategies.
organic-synthesis
chalcones
aziridination
beckmann-rearrangement
solvent-control
synthetic-methods