1,3,5-Tri- and 1,3,4,5-tetra-substituted 1,4-diazepin-2-one solid-phase synthesis

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• 1,4-Diazepin-2-ones are important heterocyclic scaffolds in medicinal chemistry.
• Developing efficient and versatile synthetic routes is crucial for accessing diverse analogs.

Purpose of the Study:

• To establish a robust solid-phase synthesis for 1,3,5-tri-substituted and 1,3,4,5-tetra-substituted 1,4-diazepin-2-ones.
• To explore the diversification of these heterocycles through N-alkylation and the use of various amino acids.

Main Methods:

• Solid-phase synthesis utilizing Wang resin and commercially available alpha- and beta-amino acids.
• Reductive amination, aminoacylation, and copper-catalyzed cascade addition reactions.
• Boc deprotection, intramolecular reductive amination, and Fmoc removal for heterocycle formation.

Main Results:

• Successful synthesis of 1,3,5-tri-substituted and 1,3,4,5-tetra-substituted 1,4-diazepin-2-ones (15-18).
• Achieved overall isolated yields ranging from 6 to 24% with purities between 81-100% (LCMS).
• Demonstrated diversification of the diazepinone core via N-alkylation.

Conclusions:

• The developed solid-phase strategy provides an efficient route to diverse 1,4-diazepin-2-one derivatives.
• This method employs inexpensive starting materials and robust chemical transformations.
• The synthesized compounds hold potential for further investigation in drug discovery programs.