Solid phase approaches to N-heterocycles using a sulfur linker cleaved by SmI2

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Solid-phase synthesis is crucial for efficient drug discovery and library generation.
• Developing versatile linkers is key to expanding the scope of solid-phase methodologies.
• Alpha-hetero-atom substituted carbonyl (HASC) linkers offer unique reactivity for synthetic transformations.

Purpose of the Study:

• To introduce and evaluate a novel sulfur HASC linker for solid-phase synthesis.
• To demonstrate the linker's utility in constructing oxindole and tetrahydroquinolone scaffolds.
• To showcase the traceless cleavage of the linker using samarium(II) iodide.

Main Methods:

• Solid-phase synthesis utilizing a sulfur HASC linker.
• Pummerer cyclization for oxindole synthesis.
• Microwave-assisted Heck reaction followed by Michael cyclization for tetrahydroquinolone synthesis.
• Traceless cleavage of the linker via samarium(II) iodide reduction.

Main Results:

• Successful synthesis of oxindoles via solid-phase Pummerer cyclization.
• Efficient construction of tetrahydroquinolones using microwave-assisted Heck and Michael reactions.
• Demonstration of traceless linker cleavage, preserving the integrity of the synthesized compounds.
• Compatibility of the linker system with multiple reaction types.

Conclusions:

• The sulfur HASC linker is a versatile tool for solid-phase synthesis.
• The developed routes are efficient for generating libraries of oxindoles and tetrahydroquinolones.
• The traceless cleavage method simplifies purification and enhances the utility of the linker for combinatorial chemistry.