Hindered dialkyl ether synthesis with electrogenerated carbocations

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Electrochemistry

Background:

• Hindered ethers are valuable in medicinal chemistry due to their metabolic stability.
• Conventional synthesis of hindered ethers is challenging, limiting their accessibility.
• Underexplored chemical space of hindered ethers presents synthetic bottlenecks.

Purpose of the Study:

• To develop a simple and efficient route for synthesizing hindered ethers.
• To explore the utility of electrochemically generated carbocations in organic synthesis.
• To overcome limitations of traditional methods in accessing hindered ether motifs.

Main Methods:

• Electrochemical oxidation of carboxylic acids to generate carbocations.
• Reaction of carbocations with alcohol donors under non-acidic conditions.
• Interception of carbocations with nucleophiles to form hindered alcohols and alkyl fluorides.

Main Results:

• A novel electrochemical method for hindered ether synthesis was established.
• Over 80 diverse hindered ethers were prepared, demonstrating broad applicability.
• The method successfully addressed synthetic bottlenecks in 12 chemical scaffolds, improving yields and reducing steps.
• Hindered alcohols and alkyl fluorides were also synthesized using carbocation intermediates.

Conclusions:

• Electrochemistry provides a powerful tool for accessing highly reactive intermediates under mild conditions.
• This method offers significant efficiency improvements for synthesizing valuable hindered ethers and related compounds.
• The developed reaction manifold overcomes previous synthetic limitations, enabling access to previously inaccessible chemical structures.