Solid-phase synthesis of urea and amide libraries using the T2 triazene linker

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Solid-Phase Synthesis

Background:

• Solid-phase synthesis is crucial for combinatorial chemistry and drug discovery.
• Novel linkers are needed to expand the scope and efficiency of solid-phase synthesis.
• Existing linkers may have limitations in terms of stability or cleavage conditions.

Purpose of the Study:

• To develop a novel backbone amide linker for immobilizing primary amines on solid support.
• To demonstrate the utility of this linker for synthesizing libraries of ureas and amides.
• To evaluate the efficiency and yield of the developed synthetic methodology.

Main Methods:

• Immobilization of primary amines onto Merrifield resin using a two-step triazene linkage (T2-linker).
• Reaction of immobilized amines with isocyanates to form urea derivatives.
• Acylation with acid chlorides or anhydrides to form backbone amide derivatives.
• Cleavage from the resin using trimethylsilyl chloride or trifluoroacetic acid.

Main Results:

• Successful synthesis of resin-bound urea and backbone amide derivatives.
• Cleavage yielded ureas and amines/amides in library format with high purity and good overall yields.
• Altogether 60 examples were synthesized, including manual and automated synthesis.
• A 4x4 member library was successfully synthesized on a Bohdan Neptune synthesizer.

Conclusions:

• The novel backbone amide linker is effective for solid-phase synthesis of diverse ureas and amides.
• The methodology allows for efficient library generation in high purity and good yields.
• This approach expands the toolkit for combinatorial chemistry and the synthesis of small molecules.