Testing the limits of radical-anionic CH-amination: a 10-million-fold decrease in basicity opens a new path to
Quintin Elliott1, Gabriel Dos Passos Gomes1, Christopher J Evoniuk1
1Department of Chemistry and Biochemistry, Florida State University Tallahassee Florida 32306 USA alabugin@chem.fsu.edu.
Chemical Science
|June 7, 2021
Summary
This study introduces a new method for intramolecular C-H amidation using amides, achieving "reductant upconversion" and forming hydroxyisoindolines. The reaction uses molecular oxygen and TEMPO to activate less reactive amides.
Area of Science:
- Organic Chemistry
- Catalysis
- Reaction Mechanisms
Background:
- Intramolecular C-H amidation is crucial for synthesizing nitrogen-containing heterocycles.
- Activating less nucleophilic N-anions like amides for C-H functionalization remains a significant challenge.
- Existing methods often require harsh conditions or pre-functionalized substrates.
Purpose of the Study:
- To develop a novel method for intramolecular C-H amidation of unprotected amides.
- To elucidate the reaction mechanism, including the role of radical intermediates and reductant upconversion.
- To expand the scope of N-anions participating in C-H functionalization reactions.
Main Methods:
- Utilizing potassium tert-butoxide (t-BuOK) as a base and molecular oxygen as an oxidant.
- Employing N,N-dimethylformamide (DMF) as a solvent and TEMPO as an additive.
- Investigating the reaction pathway through experimental studies and computational analysis.
Main Results:
- Successful intramolecular C-H amidation of amides to form hydroxyisoindolines under mild conditions.
- Demonstrated "reductant upconversion" where a weak reductant is converted to a stronger one.
- Identified a novel mechanism involving radical-anion intermediates, C-N bond formation, and subsequent C-H oxidation.
- TEMPO additive was found to activate less reactive amides, broadening the substrate scope.
Conclusions:
- A new, efficient method for synthesizing hydroxyisoindolines from unprotected amides has been established.
- The study provides fundamental insights into radical-mediated C-H functionalization and reductant upconversion.
- This work offers a versatile platform for accessing complex nitrogen-containing compounds.
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