Indole Synthesis from an Alkynyl-Containing Conjugated System: Substrate Scope and Application in Total Synthesis

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• The indole scaffold is a crucial structural motif found in numerous natural products and pharmaceuticals.
• Efficient and versatile synthetic routes to access substituted indoles are highly sought after in organic synthesis.

Purpose of the Study:

• To develop a novel, efficient, and mild synthetic method for the rapid assembly of the indole scaffold.
• To explore both intramolecular and intermolecular annulation strategies for indole synthesis.
• To demonstrate the practical utility of the developed method through total synthesis of target molecules.

Main Methods:

• A one-pot procedure involving intramolecular aza-Michael addition followed by alkene isomerization.
• Formal intermolecular (4 + 1) annulation of ortho-aminobenzyl bromide with alkynyl-containing conjugated systems.
• Utilized mild reaction conditions and a broad range of functionalized substrates.

Main Results:

• Successfully synthesized indole scaffolds with an electron-withdrawing group on the C2 side chain.
• Demonstrated broad substrate scope including aldehydes, ketones, esters, amides, phosphonates, and sulfones.
• Achieved efficient total syntheses of 4,4'-dimethylindigo (6 steps) and quindoline (5 steps).

Conclusions:

• The developed methodology provides a synthetically practical and efficient route to indole derivatives.
• The method's versatility and mild conditions make it valuable for constructing complex indole-containing compounds.
• The successful total syntheses highlight the method's applicability in advanced organic synthesis.