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Bicyclo[1.1.1]pentane Ketones via Friedel-Crafts Acylation
Karolina Urbańska1, Freya Ritterling1, Brendan Twamley2
1School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin, 152-160 Pearse Street, Dublin D02 R590, Ireland.
The Journal of Organic Chemistry
|December 22, 2025
Summary
Researchers developed a new Friedel-Crafts acylation method to synthesize bicyclo[1.1.1]pentane (BCP) ketones. This efficient protocol provides access to novel BCP-containing compounds for medicinal chemistry applications.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Chemical Synthesis
Background:
- Bicyclo[1.1.1]pentane (BCP) is a rigid, 3D hydrocarbon valuable as a phenylene and acetylene bioisostere in drug design.
- Efficient synthesis of BCP derivatives is crucial for exploring its pharmaceutical potential.
- Existing methods for BCP ketone synthesis are limited in scope and rely on expensive catalysts.
Purpose of the Study:
- To develop a novel, efficient, and cost-effective method for synthesizing BCP mono- and diketones.
- To establish a Friedel-Crafts acylation protocol using BCP acyl chlorides for functionalizing (hetero)aromatic systems.
- To explore the scope and utility of the new method in medicinal chemistry.
Main Methods:
- Developed a Friedel-Crafts acylation reaction utilizing BCP acyl chlorides and various (hetero)aromatic hydrocarbons.
- Optimized reaction conditions to maximize yield and substrate scope.
- Characterized synthesized BCP mono- and diketones and explored their reactivity and potential applications.
Main Results:
- Successfully synthesized 35 novel BCP mono- and diketones, including the first examples of diaromatic BCP 1,3-diketones.
- Demonstrated the utility of the method through 7 examples of postsynthetic modifications.
- Reported the synthesis of a BCP analogue of the drug fenofibrate.
- Investigated noncovalent interactions in the solid state using Hirshfeld analysis.
Conclusions:
- The developed Friedel-Crafts acylation protocol offers a valuable and accessible route to diverse BCP-containing compounds.
- This method significantly expands the chemical space accessible for BCP bioisosteres in drug discovery.
- The synthesized compounds and methodology hold promise for advancing medicinal chemistry research.
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