Passerini reaction

Passerini reaction
Named after	Mario Passerini
Reaction type	Carbon-carbon bond forming reaction
Identifiers
Organic Chemistry Portal	passerini-reaction
RSC ontology ID	RXNO:0000244

The Passerini reaction is a chemical reaction involving an isocyanide, an aldehyde (or ketone), and a carboxylic acid to form a α-acyloxy amide.^[1]^[2]^[3]^[4]^[5] This addition reaction is one of the oldest isocyanide-based multicomponent reactions and was first described in 1921 by Mario Passerini in Florence, Italy.^[6]^[7] It is typically carried out in aprotic solvents but can alternatively be performed in water, ionic liquids, or deep eutectic solvents.^[7] It is a third order reaction; first order in each of the reactants. The Passerini reaction is often used in combinatorial and medicinal chemistry with recent utility in green chemistry and polymer chemistry.^[6]^[8]^[9] As isocyanides exhibit high functional group tolerance, chemoselectivity, regioselectivity, and stereoselectivity, the Passerini reaction has a wide range of synthetic applications.^[6]^[10]^[11]^[12]

Concerted mechanism

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

A concerted mechanism, seen in S_N2 and Diels−Alder reactions, is theorized to occur when the Passerini reagents are present at high concentration in aprotic solvents.^[10]

This mechanism involves a trimolecular reaction between the isocyanide, carboxylic acid, and carbonyl in a sequence of nucleophilic additions. The reaction proceeds first through an imidate intermediate and then undergoes Mumm rearrangement to afford the Passerini product.^[13]^[14]

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

Ionic mechanism

In polar solvents, such as methanol or water, 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]

Reaction control

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]

Applications

Apart from forming α-acyloxy amide products, the Passerini reaction can be used to form heterocycles, polymers, amino acids, and medicinal products.

Heterocycles

Isocoumarin structure, a heterocycle afforded by a post-Passerini cyclization reaction.

The original Passerini reaction produces acyclic depsipeptides which are labile in physiological conditions. To increase product stability for medicinal use, post-Passerini cyclization reactions have been used to afford heterocycles such as β-lactams, butenolides, and isocoumarins.^[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]

Polymers

Dendrimer general structure, a type of polymer that the Passerini reaction forms.

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 form sequence-defined polymers.^[24] Bifunctional substrates can be used to undergo post-polymerization modification or serve as precursors for polymerization.^[10]^[11]^[8] As this reaction has high functional group tolerance, the polymers created using this reaction are widely diverse with tuneable properties.^[20] Macromolecules that have been produced with this reaction include macroamides, macrocyclic depsipeptides, three-component dendrimers and three-armed star branched mesogen core molecules.^[12]

Amino acids and pharmaceuticals

Passerini reaction has been employed for the formation of structures like α-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 as telaprevir (VX-950), an antiviral sold by Vertex Pharmaceuticals and Johnson & Johnson.^[12]