Copper-Catalyzed γ-C(sp³)-H Lactamization and Iminolactonization

Area of Science:

• Organic Chemistry
• Synthetic Chemistry

Background:

• γ-Lactamization reactions for pyrrolidinone synthesis are challenging, especially for aliphatic amides.
• Existing methods using cyclometallation, C-H insertion, or radical C-H abstraction have limitations.

Purpose of the Study:

• To develop a practical and efficient copper-catalyzed method for γ-C(sp3)-H lactamization and iminolactonization of aliphatic amides.
• To achieve switchable selectivity between γ-lactams and γ-iminolactones.
• To synthesize structurally diverse lactams and iminolactones.

Main Methods:

• Copper-catalyzed γ-C(sp3)-H functionalization of tosyl-protected aliphatic amides.
• Utilized Selectfluor as the sole oxidant.
• Employed two distinct sets of reaction conditions to control selectivity.

Main Results:

• Successfully achieved copper-catalyzed γ-lactamization and iminolactonization.
• Demonstrated switchable selectivity for either γ-lactams or γ-iminolactones.
• Synthesized a variety of spiro-, fused-, and bridged-lactams/iminolactones, and isoindolinones.
• Showcased further derivatization into γ-amino acids, δ-amino alcohols, and pyrrolidines.

Conclusions:

• Developed a versatile and practical method for accessing γ-lactams and γ-iminolactones.
• The method provides access to valuable synthetic intermediates for biologically important molecules.
• Offers a new strategy for pyrrolidinone synthesis and related heterocycles.