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Accelerated click reactions using boronic acids for heterocyclic synthesis in microdroplets
Jyotirmoy Ghosh1, R Graham Cooks1
1Department of Chemistry, Purdue University 560 Oval Drive West Lafayette IN 47907 USA cooks@purdue.edu.
Chemical Science
|April 25, 2025
Summary
This study introduces accelerated click chemistry using boronic acids in microdroplets, enabling reactions without catalysts or high temperatures. These novel reactions are significantly faster and applicable to drug derivative synthesis.
Area of Science:
- Organic Chemistry
- Chemical Engineering
- Materials Science
Background:
- Click chemistry offers simplicity and versatility but often requires harsh conditions like high temperatures and catalysts.
- Condensation-based click reactions face limitations hindering broader applications.
Purpose of the Study:
- To develop a catalyst-free, ambient condition method for accelerated click reactions.
- To explore the use of boronic acids in microdroplets for enhanced reaction rates.
- To demonstrate the application of these reactions in late-stage functionalization for drug discovery.
Main Methods:
- Utilized microdroplets containing 2-formyl phenylboronic acid (2-FPBA) and substituted amines.
- Conducted reactions under ambient conditions without external catalysts.
- Analyzed reaction products using Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR) spectroscopy.
Main Results:
- Achieved click reactions three orders of magnitude faster than bulk reactions.
- Synthesized diverse multi-step click products including iminoboronates, boroxines, thiazolidines, and diazaborines.
- Identified the microdroplet air-liquid interface as a superacidic and drying surface facilitating dehydration.
Conclusions:
- Microdroplet environments accelerate click chemistry via a superacidic air-liquid interface.
- This method provides a novel, efficient approach for synthesizing complex molecules.
- Demonstrated utility in late-stage functionalization for creating antihistamine drug derivatives.
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