What Is Passerini Reaction?
The Passerini reaction is a one-pot, three-component reaction (MCR) of an isocyanide, a carbonyl compound, and a carboxylic acid to give an α-acyloxyamide, first reported by the Italian chemist Mario Passerini in 1921 (Fig 1). It was one of the first MCRs ever reported, predating the Ugi reaction by several decades.
This reaction has high atom economy, simplicity of operation, and great potential for the rapid generation of molecular complexity and diversity from simple starting materials. The α-acyloxyamide product is a privileged structure found in many pharmaceuticals, agrochemicals, and materials, and can serve as a versatile building block for further synthetic elaboration.
- Reactants: Isocyanides, carbonyl compounds, carboxylic acids.
- Products: α-Acyloxyamides (α-acyloxy carboxamides).
- Reaction Type: Multi-component reaction, condensation, addition-rearrangement.
- Related Reaction: Ugi reaction.
- Experimental Tips:
a) Due to its multi-component nature, mild and easy reaction conditions, and diverse product structures, the Passerini reaction is particularly suitable for parallel synthesis to construct compound libraries and diversity-oriented pseudo-natural product synthesis, such as libraries of dehydrogenated amino acid derivatives.
b) Both the aldehyde or ketone and the carboxylic acid components in the Passerini reaction can be varied. Using inorganic acids can be used to synthesize α-hydroxyamides. Using keto acids allows the Passerini reaction to be used for the synthesis of cyclic compounds. Phenols can also serve as the acidic component in the Passerini reaction, making it suitable for O-arylation Passerini reactions.
Fig 1. Passerini reaction and its mechanism. [1]
Mechanism of Passerini Reaction
The Passerini reaction is not a simple stepwise condensation but a convergent mechanism that proceeds through a sequence of nucleophilic additions and rearrangements.
- Step 1: Protonation and Addition. The carboxylic acid protonates the electrophilic carbon of the carbonyl compound, enhancing its electrophilicity. The nucleophilic carbon of the isocyanide then attacks this activated carbonyl carbon, forming a nitrilium intermediate. This is the rate-determining step.
- Step 2: Nitrilium Ion Formation. The key intermediate is a cationic nitrilium ion. This highly reactive species is efficiently trapped.
- Step 3: Nucleophilic Trapping. The carboxylate anion (the conjugate base of the carboxylic acid) acts as a nucleophile and attacks the electrophilic carbon of the nitrilium ion.
- Step 4: Tautomerization. The resulting adduct undergoes a spontaneous [1,3]-O→N acyl transfer, known as a Mumm rearrangement, to yield the stable, observed α-acyloxyamide product. This rearrangement is irreversible and drives the reaction to completion.
Application Examples of Passerini Reaction
- Example 1: Na Liu et al. reported a tandem reaction strategy based on the in-situ capture of isocyanides, the Passerini/Staudinger/aza-Wittig reaction, for the synthesis of heterocyclic compounds. This method avoids the storage, separation, and purification of isocyanates by synthesizing the isocyanate precursor in situ and using it immediately, thus avoiding the problems of strong odor and isocyanate decomposition caused by isocyanate exposure. [2]
- Example 2: Kristina Vlahoviček-Kahlina et al. achieved densely functionalized glycomimetic library from bis-isopropylidene-protected D-fructose-derived aldehydes with various acids and isocyanates through Passerini reaction with high yield and diastereoselectivity. [3]
Fig 2. Synthetic examples via Passerini reaction.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 424-426.
- Liu, Na, et al. The Journal of organic chemistry 84.4 (2019): 2366-2371.
- Vlahoviček-Kahlina, Kristina, et al. The Journal of Organic Chemistry 83.21 (2018): 13146-13156.
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