ThePasserini reaction is achemical reaction involving anisocyanide, analdehyde (orketone), and acarboxylic acid to form a α-acyloxyamide.^{[1][2][3][4][5]} This addition reaction is one of the oldestisocyanide-based multicomponent reactions and was first described in 1921 by Mario Passerini in Florence, Italy.^[6][7] It is typically carried out inaprotic solvents but can alternatively be performed in water, ionic liquids, ordeep eutectic solvents.^[7] It is a third order reaction; first order in each of the reactants. The Passerini reaction is often used incombinatorial andmedicinal chemistry with recent utility ingreen chemistry andpolymer chemistry.^[6][8][9] As isocyanides exhibit high functional group tolerance,chemoselectivity,regioselectivity, andstereoselectivity, the Passerini reaction has a wide range of synthetic applications.^{[6][10][11][12]}

The Passerini reaction has been hypothesized to occur through two mechanistic pathways.^[10][7][11] The reaction pathways are dependent on the solvent used.

Aconcerted mechanism, seen inS_N2 andDiels−Alder reactions, is theorized to occur when the Passerini reagents are present at high concentration inaprotic solvents.^[10]

This mechanism involves atrimolecular reaction between the isocyanide, carboxylic acid, and carbonyl in a sequence ofnucleophilic additions. The reaction proceeds first through animidate intermediate and then undergoesMumm rearrangement to afford the Passerini product.^[13][14]

As theMumm rearrangement requires a second carboxylic acid molecule, this mechanism classifies the Passerini reaction as anorganocatalytic reaction.^[14][15]

In polar solvents, such asmethanol orwater, the carbonyl is protonated before nucleophilic addition of the isocyanide, affording a nitrilium ion intermediate. This is followed by the addition of a carboxylate, acyl group transfer and proton transfer respectively to give the desired Passerini product.^[11][7]

Molecular weights of polymers synthesized through the Passerini can be controlled through stoichiometric means.^[16] For example, polymer chain length and weight can adjusted through isocyanide stoichiometry, and polymer geometry can be influenced through starting reagents.^[16][17] To facilitate the Passerini reaction between bulky, sterically hindered reagents, a vortex fluidic device can be used to induce high shear conditions. These conditions emulate the effects of high temperature and pressure, allowing the Passerini reaction to proceed fairly quickly.^[18] The Passerini reaction can also exhibit enantioselectivity. Addition of tert-butyl isocyanide to a wide variety of aldehydes (aromatic, heteroaromatic, olefinic, acetylenic, aliphatic) is achieved using a catalytic system of tetrachloride and a chiral bisphosphoramide which provides good yield and good enantioselectivities.^[19] For other types of isocyanides, rate of addition of isocyanide to reaction mixture dictates good yields and high selectivities.^[19]

Apart from forming α-acyloxyamide products, the Passerini reaction can be used to formheterocycles,polymers,amino acids, andmedicinal products.

The original Passerini reaction produces acyclicdepsipeptides which are labile in physiological conditions. To increase product stability for medicinal use, post-Passerini cyclization reactions have been used to afford heterocycles such asβ-lactams,butenolides, andisocoumarins.^[16] To enable these cyclizations, reagents are pre-functionalized with reactive groups (ex. halogens, azides, etc.) and used in tandem with other reactions (ex. Passerini-Knoevenagel, Passerini-Dieckmann) to afford heterocyclic products.^[16] Compounds like three membered oxirane and aziridine derivatives, four-membered b-lactams, and five-membered tetrasubstituted 4,5-dihydropyrazoles have been produced through this reaction.^[12]

This reaction has also been used for polymerization,monomer formation, and post-polymerization modification.^{[20][21][22][17][23]} The Passerini reaction has also been used to formsequence-defined polymers.^[24]Bifunctional substrates can be used to undergo post-polymerization modification or serve as precursors forpolymerization.^[10][11][8] As this reaction has high functional group tolerance, the polymers created using this reaction are widely diverse with tuneableproperties.^[20] Macromolecules that have been produced with this reaction include macroamides, macrocyclic depsipeptides, three-componentdendrimers and three-armed star branchedmesogen core molecules.^[12]

Passerini reaction has been employed for the formation of structures likeα-amino acids, α-hydroxy-β-amino acids, α-ketoamides, β-ketoamides, α-hydroxyketones and α-aminoxyamides.^[12] The Passerini reaction has synthesized α-Acyloxy carboxamides that have demonstrated activity as anti-cancer medications along with functionalized [C60]-fullerenes used in medicinal and plant chemistry.^[12][25] This reaction has also been used as a synthetic step in the total synthesis of commercially available pharmaceuticals such astelaprevir (VX-950), anantiviral sold by Vertex Pharmaceuticals and Johnson & Johnson.^[12]

• Ugi reaction

• Carbon-carbon bond forming reactions
• Multiple component reactions
• Name reactions
• Amide synthesis reactions

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