Passerini reaction
The Passerini reaction is a chemical reaction that involves three components: an isocyanide, an aldehyde (or ketone), and a carboxylic acid, which react together to form an α-acyloxy amide[4]. This multicomponent reaction is one of the oldest isocyanide-based reactions, first described in 1921 by Mario Passerini[4].
The reaction typically proceeds rapidly in aprotic solvents at room temperature and is known for its high yields when high concentrations of starting materials are used[1]. It is generally accepted that the reaction does not follow an ionic pathway, and hydrogen bonding is believed to play a crucial role in the formation of the presumed cyclic transition state[1]. The reaction is faster in low polarity media and is usually carried out in solvents such as dichloromethane, ethyl acetate, diethyl ether, and tetrahydrofuran[3][8]. Alcohols are not well suited as solvents for the Passerini reaction, and when it occurs as an unwanted side reaction in an Ugi process, it can be suppressed by using high polar alcohols like trifluoroethanol[8].
The mechanism of the Passerini reaction has been hypothesized to occur through two pathways, depending on the solvent used. In aprotic solvents, a concerted mechanism is theorized, involving a trimolecular reaction between the isocyanide, carboxylic acid, and carbonyl compound, proceeding through an imidate intermediate and then undergoing a Mumm rearrangement to afford the product[4]. In polar solvents, the carbonyl is protonated before nucleophilic addition of the isocyanide, leading to a nitrilium ion intermediate, followed by the addition of a carboxylate, acyl group transfer, and proton transfer to give the desired product[4].
The Passerini reaction has been employed in various synthetic applications, including the synthesis of polymers, macrocycles, heterocycles, and pharmaceuticals[2][5]. It has also been used in the total synthesis of natural products and drug-like compounds[5]. The reaction has been developed further with various modifications, such as Lewis acid catalysis and in situ oxidation of alcohols to aldehydes[5]. It has also been used in green chemistry applications and has been adapted to mechanochemical conditions[6][9].
In summary, the Passerini reaction is a versatile and widely used reaction in organic synthesis, offering a straightforward route to α-acyloxy amides with a broad scope and high functional group tolerance.
Citations:
[1] https://www.organic-chemistry.org/namedreactions/passerini-reaction.shtm
[2] https://www.sciencedirect.com/science/article/pii/S0014305723001878
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654045/
[4] https://en.wikipedia.org/wiki/Passerini_reaction
[5] https://www.eurekaselect.com/article/21679
[6] https://pubs.acs.org/doi/10.1021/sc5002116
[7] https://pubs.acs.org/doi/10.1021/acs.joc.5b00594
[8] https://pubs.rsc.org/en/content/articlehtml/2021/sc/d1sc03810a
[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10191865/
[10] https://www.sciencedirect.com/topics/chemistry/passerini-condensation
[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10167652/
[12] https://baranlab.org/images/grpmtgpdf/Demartino_Aug_03.pdf
[13] https://pubs.rsc.org/en/content/articlelanding/2022/nj/d1nj03832j/unauth
[14] https://www.sciencedirect.com/science/article/abs/pii/S0014305723001878
[15] https://pubs.acs.org/doi/10.1021/ja01225a027
[16] https://www.youtube.com/watch?v=2CBRoGOFNhI
[17] https://www.researchgate.net/figure/The-mechanism-of-the-Passerini-reaction_fig3_354957041