Net Intermolecular Silyloxypyrone-Based (5+2) Cycloadditions Utilizing Amides as Enabling and Cleavable Tethers

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Cycloaddition Reactions

Background:

• Silyloxypyrone-based (5+2) cycloadditions are valuable synthetic tools.
• Tethering strategies are crucial for controlling reactivity and product formation.
• Amine tethers have limitations in certain cycloaddition reactions.

Purpose of the Study:

• To investigate the use of amides as facilitating groups in silyloxypyrone (5+2) cycloadditions.
• To explore the scope and limitations of amide-mediated cycloadditions, including dearomative variants.
• To elucidate the mechanism and factors influencing the reaction rate.

Main Methods:

• Facile cycloaddition reactions using various amides.
• Investigation of steric and electronic effects on reaction acceleration.
• Comparison of amide tethers with amine tethers in oxidopyrylium-indole cycloadditions.
• Theoretical calculations to understand reaction mechanisms.
• Demonstration of one-pot reaction sequences including lactam opening.

Main Results:

• Amides effectively facilitated silyloxypyrone (5+2) cycloadditions, leading to net intermolecular cycloadducts.
• Steric factors, such as the use of tert-butyl amides, accelerated the reaction.
• Amides enabled dearomative oxidopyrylium-indole (5+2) cycloadditions where amine tethers failed.
• Theoretical studies supported a concerted asynchronous mechanism driven by amide-induced conformational changes.
• Successful one-pot transformations involving acylation, cycloaddition, and lactam opening were achieved.

Conclusions:

• Amide-based tethers represent a powerful advancement for silyloxypyrone (5+2) cycloadditions.
• The methodology is versatile, enabling challenging dearomative cycloadditions and subsequent functionalizations.
• Understanding the mechanistic role of amides provides a basis for further synthetic development.