Copper-Catalyzed, N-Directed Distal C(sp³)-H Functionalization toward Azepanes

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Azepanes are important heterocyclic scaffolds found in numerous pharmaceuticals and natural products.
• Efficient synthetic routes for constructing functionalized azepanes, particularly those amenable to late-stage diversification, are highly sought after.

Purpose of the Study:

• To develop a novel copper-catalyzed formal [5 + 2] aza-annulation reaction.
• To synthesize structurally diverse alkene- and alkyne-containing azepanes.
• To enable selective functionalization of unactivated C(sp³)-H bonds for late-stage modifications.

Main Methods:

• Copper-catalyzed formal [5 + 2] aza-annulation reaction.
• Utilized N-fluorosulfonamides and 1,3-dienes or 1,3-enynes as starting materials.
• Investigated a radical mechanism involving hydrogen atom transfer and radical-diene/enyne coupling.

Main Results:

• Successfully synthesized a range of alkene- and alkyne-containing azepanes with high structural diversity.
• Demonstrated selective functionalization of distal, unactivated C(sp³)-H bonds.
• Showcased broad substrate scope, including applicability to late-stage modification of pharmaceutical and natural product analogues.

Conclusions:

• The developed copper-catalyzed aza-annulation provides an efficient method for azepane synthesis.
• The reaction's ability to functionalize C-H bonds and its broad scope make it valuable for medicinal chemistry and drug discovery.
• A radical mechanism involving 1,5-hydrogen atom transfer is proposed to explain the reaction pathway.