Passerini reaction

The Passerini reaction is a

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 also be performed in ionic liquids such as water 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]}

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

Concerted mechanism

A

This mechanism involves a

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

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-

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

This reaction has also been used for polymerization,

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]

See also

• Ugi reaction

References