Solid-phase synthesis of isocoumarins: a traceless halocyclization approach

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Isocoumarins are important heterocyclic compounds with diverse biological activities.
• Developing efficient and versatile synthetic routes for isocoumarins is crucial for drug discovery.
• Solid-phase synthesis offers advantages in purification and parallel synthesis of complex molecules.

Purpose of the Study:

• To develop a straightforward and traceless solid-phase methodology for synthesizing isocoumarins.
• To enable the generation of diverse isocoumarin libraries using parallel synthesis.
• To achieve high yields and purities in the synthesized compounds.

Main Methods:

• A two-step solid-phase synthesis was employed.
• The first step involved a Sonogashira cross-coupling reaction between polymer-bound 2-bromobenzoates and terminal alkynes.
• The second step utilized an electrophile-induced halocyclization of the resulting 2-(alk-1-ynyl)benzoates.

Main Results:

• The methodology successfully synthesized 3-substituted 4-haloisocoumarins.
• The process was traceless, leaving no byproducts on the solid support.
• The polymer-bound parallel synthetic approach yielded a large diversity of compounds.
• Good to excellent yields and purities were achieved for the synthesized isocoumarins.

Conclusions:

• A robust and efficient solid-phase synthesis for isocoumarins has been established.
• This method is suitable for generating diverse libraries of isocoumarins.
• The developed methodology offers a valuable tool for accessing functionalized isocoumarins in medicinal chemistry and drug discovery.