Enabling electrochemical, decarboxylative C(sp2)-C(sp3) cross-coupling for parallel medicinal chemistry
Jennifer Morvan1, Bingqing Tang1, Pavel Ryabchuk1
1Global Discovery Chemistry, Janssen Research and Development, Turnhoutseweg 30, Beerse, 2340 Belgium.
European Journal of Medicinal Chemistry
|April 12, 2025
Summary
We developed an automated, purification-free electrochemical method to couple carboxylic acids and aryl halides. This advances C(sp2)-C(sp3) bond formation for drug discovery, enabling rapid library synthesis.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Electrochemistry
Background:
- Carboxylic acids are versatile building blocks in medicinal chemistry.
- Decarboxylative cross-coupling for C(sp2)-C(sp3) bond formation is challenging.
- Existing methods using redox-active esters (RAEs) can generate byproducts detrimental to catalysis.
Purpose of the Study:
- To develop an automated, purification-free protocol for activating carboxylic acids.
- To enable efficient electrochemical decarboxylative cross-coupling.
- To facilitate the synthesis of compound libraries, including PROTACs.
Main Methods:
- Activation of carboxylic acids as N-hydroxyphthalimide (NHPI) esters.
- High-throughput, automated electrochemical decarboxylative cross-coupling.
- Purification-free protocol design.
Main Results:
- Successful coupling of aliphatic carboxylic acids and aryl halides under mild electrochemical conditions.
- Demonstrated applicability in preparing compound libraries and PROTACs.
- Overcame limitations of previous RAE-based methods.
Conclusions:
- The developed automated protocol streamlines C(sp2)-C(sp3) bond formation.
- This method expands the utility of readily available carboxylic acids in drug discovery.
- The protocol has the potential to impact future cross-coupling strategies in pharmaceutical research.
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