The Passerini reaction has been hypothesized to occur through two mechanistic pathways.[10][7][11] The reaction pathways are dependent on the solvent used.
[edit]Proposed ionic version of the Passerini reaction mechanism.
In polar solvents, such as methanolorwater, 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]
[edit]Isocoumarin structure, a heterocycle afforded by a post-Passerini cyclyization 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
[edit]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]
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]
The antiviral drug telaprevir, the Passerini reaction is used in its synthesis.
^ abcdThe Passirini Reaction L. Banfi, R.Riva in Organic Reactions vol. 65 L.E. Overman Ed. Wiley 2005 ISBN0-471-68260-8
^ abcdTaran, Jafar; Ramazani, Ali; Joo, Sang Woo; Ślepokura, Katarzyna; Lis, Tadeusz (2014). "Synthesis of Novel a-(Acyloxy)-a-(quinolin-4-yl)acetamides by a ThreeComponent Reaction between an Isocyanide, Quinoline-4-carbaldehyde, and Arenecarboxylic Acids". Helvetica Chimica Acta. 97: 1088–1096. doi:10.1002/hlca.201300378.