Cu-Catalyzed Desaturation-Relay Imidation of 2-Piperidones

Area of Science:

• Organic Chemistry
• Catalysis
• Heterocyclic Chemistry

Background:

• Saturated heterocycles are important scaffolds in pharmaceuticals and natural products.
• Developing efficient methods for functionalizing these core structures remains a key challenge in organic synthesis.

Purpose of the Study:

• To develop a novel copper-catalyzed cascade reaction for the regioselective oxidative desaturation and imidation of saturated heterocycles.
• To explore the use of N-fluorobenzenesulfonimide (NFSI) as a dual oxidant and imidating reagent in this transformation.

Main Methods:

• Copper catalysis was employed to facilitate the cascade reaction.
• N-fluorobenzenesulfonimide (NFSI) was utilized as the key reagent.
• A range of saturated heterocyclic substrates, including piperidones, lactams, and cyclic ketones, were investigated.
• Reaction mechanisms were probed using TEMPO-trap experiments, control experiments, and density functional theory (DFT) calculations.

Main Results:

• The developed method successfully achieved regioselective oxidative desaturation and imidation of various saturated heterocycles.
• The transformation exhibited high functional group tolerance, accommodating a broad scope of substituted substrates.
• TEMPO-trap experiments, control studies, and DFT calculations provided insights into the reaction pathway, supporting a desaturation mechanism.

Conclusions:

• A novel and efficient copper-catalyzed cascade reaction for the synthesis of functionalized heterocycles has been established.
• The use of NFSI as a dual oxidant and imidating reagent offers a convenient approach for this transformation.
• The methodology holds potential for the synthesis of complex heterocyclic compounds with applications in medicinal chemistry.