Convergent Assembly of 1,4-Benzothiazide Spiroindolinones via [4 + 2] Spiroannulation Under Open-Air Conditions

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Spiroindolinones are privileged scaffolds in medicinal chemistry, exhibiting diverse biological activities.
• Developing efficient and metal-free synthetic routes to spiroindolinones is highly desirable for sustainable drug discovery.
• Isatin derivatives and aminobenzenethiols are readily available starting materials.

Purpose of the Study:

• To develop a novel, transition-metal-free synthetic protocol for 1,4-benzothiazide spiroindolinones.
• To investigate the reaction mechanism and identify key intermediates.
• To demonstrate the versatility of the synthesized compounds for further functionalization into pharmaceutically relevant scaffolds.

Main Methods:

• A one-pot [4 + 2] spirocyclization reaction between isatin-derived β-silylcarbinols and 2-aminobenzenethiols.
• Utilizing control experiments to elucidate the reaction pathway and identify intermediates such as 3-methylene oxindoles and disulfides.
• Subsequent oxidation of the spiroindolinone products to sulfone and sulfoxide derivatives.

Main Results:

• Successful synthesis of 1,4-benzothiazide spiroindolinones in decent yields via a transition-metal-free spirocyclization.
• Identification of 3-methylene oxindoles and disulfides as crucial intermediates in the tandem reaction mechanism.
• Demonstration of facile conversion of the synthesized spiroindolinones into pharmaceutically significant sulfone and sulfoxide scaffolds.

Conclusions:

• The developed protocol offers a facile and efficient metal-free approach to valuable spiroindolinone structures.
• The identified intermediates provide mechanistic insights into the tandem spirocyclization process.
• The synthesized compounds serve as versatile precursors for generating diverse pharmaceutically relevant molecules, highlighting the protocol's broad applicability.