Privileged scaffolds on demand: a Passerini-based strategy toward α-ketoamides
Michael Georgoulakis1, Ioannis Angelonidis1, Konstantinos G Froudas1
1Department of Chemistry, University of Crete, Heraklion, Greece. kneochor@uoc.gr.
Organic & Biomolecular Chemistry
|November 20, 2025
Summary
A new scalable Passerini reaction synthesizes alpha-ketoamides, important in medicine. This efficient one-pot method produces diverse compounds, including inhibitors of human 15-LOX-1.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
Background:
- Alpha-ketoamides are crucial structural motifs in medicinal chemistry.
- Existing synthetic routes for alpha-ketoamides can be limited in scope or scalability.
Purpose of the Study:
- To develop a scalable and efficient Passerini-based method for synthesizing alpha-ketoamides.
- To demonstrate the utility of the synthesized alpha-ketoamides as inhibitors of human 15-LOX-1.
Main Methods:
- Utilized a modified Passerini reaction involving p-hydroxybenzoic acid and ethanol.
- Interrupted the Mumm rearrangement to form alpha-hydroxyamides.
- Performed a one-pot oxidation to yield the target alpha-ketoamides.
- Validated the method's tolerance for diverse substrates and gram-scale synthesis.
Main Results:
- Successfully synthesized alpha-ketoamides using a scalable Passerini-based approach.
- The one-pot procedure demonstrated broad substrate scope and efficiency.
- Gram-scale synthesis was achieved, highlighting the method's practicality.
- Synthesized compounds showed inhibitory activity against human 15-LOX-1.
Conclusions:
- The developed Passerini-based method offers a scalable and versatile route to alpha-ketoamides.
- This approach provides access to potential therapeutic agents, such as 15-LOX-1 inhibitors.
- The method holds significant promise for both synthetic and medicinal chemistry applications.
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
Related Concept Videos
01:26Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction
4.0K
α-Substituted ketones or aldehydes can be synthesized from enamines by the Stork enamine reaction, named after its pioneer Gilbert Stork. Enamines are useful synthetic intermediates where the lone pair on nitrogen is in conjugation with the C=C bond. They resemble enolate ions, as the resonance forms of both species have a nucleophilic α carbon.
4.0K
01:28Preparation of 1° Amines: Gabriel Synthesis
4.5K
Direct alkylation is not a suitable method for synthesizing amines because it produces polyalkylated products. Gabriel synthesis is the most preferred method to exclusively make primary amines. The method uses phthalimide, which contains a protected form of nitrogen that participates in alkylation only once to predominantly give primary amines.
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
Strong bases like NaOH or KOH deprotonate the phthalimide to form the corresponding anion, which acts as a nucleophile. Further, the anion attacks an...
4.5K
01:26Preparation of 1° Amines: Hofmann and Curtius Rearrangement Mechanism
4.0K
The Hofmann and Curtius rearrangement reactions can be applied to synthesize primary amines from carboxylic acid derivatives such as amides and acyl azides. In the Hofmann rearrangement, a primary amide undergoes deprotonation in the presence of a base, followed by halogenation to generate an N-haloamide. A second proton abstraction produces a stabilized anionic species, which rearranges to an isocyanate intermediate via an alkyl group migration from the carbonyl carbon to the neighboring...
4.0K
01:07Preparation of 1° Amines: Hofmann and Curtius Rearrangement Overview
3.6K
In the presence of an aqueous base and a halogen, primary amides can lose the carbonyl (as carbon dioxide) and undergo rearrangement to form primary amines. This reaction, called the Hofmann rearrangement, can produce primary amines (aryl and alkyl) in high yields without contamination by secondary and tertiary amines.
3.6K
01:29Preparation of Amides
3.9K
Amides are synthesized by treating carboxylic acids with amines in the presence of dehydrating agents like dicyclohexylcarbodiimide (DCC).
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
The DCC-promoted synthesis of amides begins with the protonation of DCC by carboxylic acid. The protonation makes it a better acceptor. Next, the addition of carboxylate to the protonated carbodiimide gives a reactive acylating agent.
Subsequently, the amine acts as a nucleophile that attacks the acylating agent to form a tetrahedral intermediate. In the...
3.9K
01:07Alkylation of β-Ketoester Enolates: Acetoacetic Ester Synthesis
4.4K
Acetoacetic ester synthesis is a method to obtain ketones from alkyl halides and β-keto esters. The reaction occurs in the presence of an alkoxide base that abstracts the acidic proton of the β-keto esters. The step results in an enolate ion which is doubly stabilized. The enolate then reacts with an alkyl halide via the SN2 process to produce an alkylated ester intermediate with a new C–C bond. The hydrolysis of the intermediate, followed by acidification, results in an...
4.4K