Free-amine-directed Ru(II)-catalyzed peri-selective C-H activation and annulation via ring-strain release

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Developing efficient synthetic routes to complex heterocyclic compounds is crucial for drug discovery.
• Medium-sized lactams are valuable scaffolds in medicinal chemistry but are often challenging to synthesize.
• Ruthenium(II)-catalyzed C-H activation offers a powerful tool for constructing complex molecular architectures.

Purpose of the Study:

• To develop a novel Ruthenium(II)-catalyzed method for synthesizing tricyclic naphtho-fused medium-sized lactams.
• To explore the scope and regioselectivity of the C-H activation/annulation reaction.
• To demonstrate the utility of this method for accessing diverse seven-membered ring frameworks.

Main Methods:

• Ruthenium(II)-catalyzed *peri*-selective C-H activation/annulation reaction.
• Utilized α-naphthylamines as substrates.
• Employed alkylidene β-lactones and β-lactams as reaction partners.
• Investigated the role of the free amine directing group in regioselectivity.
• Analyzed the ring strain release mechanism in lactone/lactam annulation.

Main Results:

• Achieved rapid access to diverse tricyclic naphtho-fused medium-sized lactams.
• Demonstrated *peri*-selectivity in the C-H activation process.
• Regioselectivity was effectively controlled by the free amine directing group.
• Controlled ring strain release facilitated the formation of seven-membered frameworks.
• Obtained products in high yields, showcasing the efficiency of the method.

Conclusions:

• The developed Ruthenium(II)-catalyzed reaction provides an efficient and versatile pathway to complex tricyclic naphtho-fused medium-sized lactams.
• The methodology allows for controlled regioselectivity and the formation of diverse seven-membered ring systems.
• This approach holds significant potential for the synthesis of novel pharmaceutical agents and complex organic molecules.