Photoinduced Lactamization/Truce-Smiles Rearrangement Cascade Enables Access to Lactam-Fused β-Arylethylamines

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• The radical Truce-Smiles rearrangement (TSR) is a key 1,4-aryl migration method.
• β-arylethylamine structures are crucial pharmacophores in drug discovery.
• Efficient and selective synthesis of these motifs remains a challenge.

Purpose of the Study:

• To develop a diastereoselective synthesis of lactam-fused arylethylamines.
• To explore an intramolecular lactamization/TSR rearrangement cascade.
• To achieve this synthesis under metal- and photocatalyst-free conditions.

Main Methods:

• Utilized a linear sulfonamide substrate for cascade reaction.
• Employed an electron donor-acceptor (EDA) complex to drive the reaction.
• Characterized the reaction mechanism involving two consecutive 5-exo-trig cyclizations.

Main Results:

• Achieved diastereoselective synthesis of lactam-fused arylethylamines.
• Demonstrated that a rigid cyclic transition state governs stereochemical outcomes.
• Showcased excellent functional group compatibility and high diastereoselectivity.

Conclusions:

• The developed cascade reaction offers a step-economical route to valuable β-arylethylamine pharmacophores.
• The metal- and photocatalyst-free approach enhances synthetic efficiency and sustainability.
• This method provides a powerful tool for accessing complex arylethylamine derivatives.