The solid-phase Nicholas reaction: scope and limitations.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Solid-phase synthesis offers advantages in purification and automation for creating chemical libraries.
• The Sonogashira and Nicholas reactions are powerful tools for carbon-carbon bond formation.

Purpose of the Study:

• To develop a robust solid-phase synthesis of alpha-substituted alkynes.
• To explore the scope of nucleophiles applicable in the solid-phase Nicholas reaction.
• To optimize the sequential Sonogashira/Nicholas reaction for efficient library generation.

Main Methods:

• Sequential Sonogashira coupling followed by Nicholas reaction on a solid support.
• Investigation of various carbon, oxygen, nitrogen, sulfur, fluoride, and hydride nucleophiles.
• Optimization of reaction conditions including Lewis acid, Sonogashira catalyst, temperature, time, and decomplexation.

Main Results:

• Successful preparation of two libraries of alpha-substituted alkynes.
• Demonstrated broad scope of nucleophiles for the solid-phase Nicholas reaction.
• Optimized five-step sequence completed in a single day.

Conclusions:

• The developed solid-phase strategy provides an efficient route to diverse alpha-substituted alkynes.
• This methodology is suitable for rapid library synthesis in drug discovery and chemical biology.