Copper-Catalyzed Asymmetric Sulfilimination Enabled by Chiral Bisoxazoline Ligands
Created on 02.06
Copper-Catalyzed Asymmetric Sulfilimination Enabled by Chiral Bisoxazoline Ligands
– Collaborative Research by Shaanxi Normal University Li Xingwei, Xiao Jichao / Northeast Normal University Zheng Guangfan Teams Published in CCS Chemistry
1. Research Background and Significance
Chiral sulfilimines, as nitrogen analogues of sulfoxides, serve as privileged structural motifs in bioactive molecules and versatile synthetic intermediates. However, their catalytic enantioselective synthesis remains a significant challenge. Conventional methods often rely on polar mechanisms and pre-activated coupling reagents, lacking efficient strategies for direct sulfilimination via inert C(sp³)–H or C–C bond functionalization. Recently, the collaborative teams developed a copper-catalyzed asymmetric sulfilimination method using chiral bisoxazoline ligands, employing readily available sulfonamides as both sulfur and nitrogen sources. Through nitrogen-centered radical-mediated 1,5-hydrogen atom transfer (HAT) and β-C–C bond cleavage, they achieved remote benzylic C–H sulfilimination of N-fluorocarboxamides and asymmetric remote sulfilimination of cyclobutanone oxime esters. This strategy represents the first radical-based enantioselective C–H/C–C sulfilimination, providing a new paradigm complementary to traditional polar mechanisms.
2. Methodology and Reaction Design
Key Innovations:
- Nitrogen Radical Pathway: Enables activation of inert C–H/C–C bonds via radical relay, bypassing traditional substrate pre-functionalization requirements.
- Dual Sulfur/Nitrogen Source: Sulfonamides act as economical and atom-efficient reagents.
- Two Reaction Modes: Remote C–H Sulfilimination: Via 1,5-HAT process with N-fluorocarboxamides. C–C Bond Cleavage Sulfilimination: Using cyclobutanone oxime esters as radical precursors.
Standard Reaction Conditions:
- Catalyst: Cu(OTf)₂ (10–20 mol%)
- Ligand: Chiral bisoxazoline (12–24 mol%)
- Substrates: N-Fluorocarboxamides or cyclobutanone oxime esters + sulfonamides
- Base: DBU or MTBD (2.0 equiv)
- Solvent: Ethyl acetate or 1,4-dioxane
- Temperature: 40–60°C
3. Advantages of Chiral Bisoxazoline Ligands
- Broad Substrate and Reaction Compatibility The Cu(OTf)₂/bisoxazoline catalytic system demonstrates exceptional versatility: Compatible with both C–H functionalization and C–C cleavage pathways. Maintains high stereocontrol in different solvents (EtOAc, dioxane) and bases (DBU, MTBD) without significant ligand modification.
- Enhanced Stability and Synergistic Catalysis Overcomes catalyst deactivation caused by strong sulfonamide coordination. Promotes S(II)/S(IV) tautomerization and single-electron transfer processes via precise copper–ligand cooperation. Suppresses non-catalytic C–S bond formation side reactions, ensuring excellent chemoselectivity.
- Late-Stage Functionalization of Complex Molecules Successfully applied to the asymmetric sulfilimination of drug derivatives and natural products: Gemfibrozil, estrone, empagliflozin intermediates, and D-glucofuranose derivatives. High yields and enantioselectivity, providing practical access to chiral sulfilimine-containing bioactive compounds.
4. Substrate Scope and Functional Group Tolerance
The methodology exhibits remarkable breadth:
- N-Fluorocarboxamides: Tolerates electron-donating/withdrawing groups on aromatic rings.
- Cyclobutanone Oxime Esters: Compatible with alkyl, aryl, and heteroaryl substituents.
- Sulfonamides: Various aromatic and aliphatic sulfonamides proceed efficiently.
5. Industrial Support and Ligand Availability
To facilitate further research, Anhui Kaitai Laibo offers multiple chiral bisoxazoline ligands and custom synthesis services.
6. Publication Details
Title: Copper-Catalyzed Asymmetric Sulfilimination of Diverse Radical Precursors via Nitrogen-Centered Radical-Enabled C–H and C–C Cleavage
Authors: Bin Wei, Jiangtao Wang, Lihan Zhu, Xiao-Xi Li, Kehan Jiao, Jichao Xiao, Guangfan Zheng, Xingwei Li*
Journal: CCS Chemistry
DOI: 10.31635/ccschem.025.202506960