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A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species
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Mild Sustainable Amide Alkylation Protocol Enables a Broad Orthogonal Scope
Jason P Hibbard1, Jessalyn G Yam1, Eyad B Alsalek1
1Department of Chemistry, University of California, Riverside, 501 Big Springs Road, Riverside, California92521, United States.
The Journal of Organic Chemistry
|August 24, 2022
Summary
A new sustainable method efficiently couples alkyl halides with amides under mild conditions. This approach avoids harsh bases, high temperatures, and organometallic catalysts, yielding valuable alkylated amides with broad substrate compatibility.
Area of Science:
- Organic Chemistry
- Synthetic Chemistry
- Medicinal Chemistry
Background:
- Amide alkylation is crucial for synthesizing bioactive molecules.
- Existing methods often require harsh conditions (strong bases, high temperatures) or organometallic catalysts.
- These limitations restrict the scope and applicability of amide alkylation.
Purpose of the Study:
- To develop a mild and sustainable protocol for coupling primary alkyl halides with amides.
- To establish an orthogonal method that circumvents the drawbacks of current synthetic strategies.
- To provide a versatile route to secondary and tertiary amides.
Main Methods:
- Utilizing potassium phosphate (K3PO4) as a facilitator.
- Employing mild reaction conditions, avoiding strong bases and high temperatures.
- Coupling primary alkyl chlorides and bromides with various amides.
Main Results:
- Successful synthesis of secondary and tertiary amides in good to excellent yields.
- Demonstrated broad scope with no significant limitations based on steric or electronic properties of coupling partners.
- Achieved high orthogonality compared to existing methodologies.
Conclusions:
- The developed protocol offers a mild, sustainable, and versatile approach to amide alkylation.
- This method expands access to important amide scaffolds found in pharmaceuticals and natural products.
- The protocol's robustness and broad scope make it a valuable tool for synthetic chemists.
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