A Photocatalytic Approach to Radical 1-(Trifluoromethyl)cyclopropanation

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Photochemistry

Background:

• The trifluoromethylcyclopropyl group is a privileged scaffold in medicinal chemistry.
• Efficient methods for incorporating this moiety are crucial for drug discovery.
• Existing methods often require harsh conditions or have limited substrate scope.

Purpose of the Study:

• To develop a simple and scalable protocol for synthesizing a novel reagent for trifluoromethylcyclopropanation.
• To demonstrate the utility of this reagent for incorporating the trifluoromethylcyclopropyl group into diverse organic molecules.
• To highlight the reagent's applicability in preparing medicinally relevant building blocks.

Main Methods:

• Multigram-scale synthesis of 5-(1-(trifluoromethyl)cyclopropyl)dibenzothiophenium triflate.
• Mild photochemical conditions for radical generation.
• Application of the reagent to various (hetero)arenes and silyl enol ethers.

Main Results:

• The benchtop-stable reagent efficiently releases 1-(trifluoromethyl)cyclopropyl radicals.
• Straightforward incorporation of the trifluoromethylcyclopropyl chemotype at non-functionalized positions.
• Broad substrate scope, excellent functional group tolerance, high regioselectivity, and useful yields were achieved.

Conclusions:

• The developed protocol provides a simple and effective method for trifluoromethylcyclopropanation.
• The reagent is highly suitable for synthesizing medicinally relevant building blocks.
• This work expands the synthetic toolbox for accessing valuable fluorinated organic compounds.