Passerini studies

The power of the Passerini and Ugi reactions in constructing polyfunctional molecules has been well appreciated since the early studies. The classical Passerini and Ugi reactions afford a-acyloxy carboxamides and a-acylamino amides respectively, that can be easily manipulated by post-condensation reactions, generating molecular diversity for drug discovery and natural product synthesis [22], This strategy has been widely applied to the synthesis of natural peptides and open-chain peptide mimetics covered in this section. 

In a related study Denmark and Fan [22] investigated chiral Lewis base-catalyzed enantioselective a-additions of isocyanides to aldehydes in a Passerini-type reaction (Scheme 9.14). The development of the reaction was based on the concept of Lewis base activation of a weak Lewis acid such as SiCl4 forming a trichlorosilyl-Lewis base adduct which is capable of activating aldehydes towards nucleophilic attack. 

In addition to the rodent bioassay, the aromatic amines have been studied in the shorter term test Salmonella typhimurium mutagenicity as well as in a variety of acute toxicity assays. A number of QSARs have been generated from such data. The work of Hansch in recent years has demonstrated that the comparison of the QSAR models obtained in different systems, by putting them in a wider perspective, can provide useful clues in the study of the mechanisms of action of individual chemical classes, and can give precious hints on how appropriate the specific models and parameters selected are (Hansch, 2001 Hansch et al., 2002). An exercise of the mechanistic comparison of QSARs has been performed on aromatic amines (Benigni and Passerini, 2002). The results are detailed below. 

These proceeded in good to excellent yields just by stirring the emulsion in air no catalyst or other additive was required/ The organic acid obtained could then be reacted in the same pot in water in a Passerini reaction with an isocyanide and some unoxidized aldehyde. This study exemplifies an interesting control mechanism for tandem reactions, by using the phase behaviour of the reagents to control the reactivity. 

Bossio, R., Marcaccini, S., Pepino, R. Studies on isocyanides and related compounds. Synthesis of oxazole derivatives via the Passerini reaction. Liebigs Ann. Chem. 1991, 1107-1108. 

Addition of TiCl4 to a solution of trimethylsiloxyphenylisocyanide in //-hexane yields the air sensitive octahedral diisocyanide complex TiCl4(CNR)2 (Scheme 114). This complex crystallizes with one molecule of //-hexane. Its molecular structure has been determined by X-ray crystallography.227 The formations of isocyanide titanium complexes are studied as species related with the Passerini reaction assisted by TiCl4. Three classes of compounds were identified and exemplified by isolated complexes (Scheme 115).228... 

Isocyanides have attracted much attention in synthetic organic chemistry, and have led to the development of a variety of useful synthetic transformations [1]. In particular, carbon-carbon bond forming reactions using isocyanides as key reagents have been extensively studied during the past 50 years, as they allow the realization of useful multi-component assembly reactions, such as the Ugi and Passerini reactions [2]. These have once again been highlighted in recent years with the development of combinatorial chemistry. The characteristic reactions of isocyanides are mostly ascribed to the unique reactivity of the isocyano carbon atom, which can be represented by a divalent, carbene-like electronic structure (Scheme 1). In this respect,... 

Ponticelli C, Zucchelli P, Passerini P, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int 1995 48 1600-1604. 

Two papers dealing with the ionization of di-323 and tri-323,324 substituted sulphamides have appeared. In the first study323 potentiometric and UV methods were used to examine the equilibria (shown in equation 101) in 60% v/v ethanol-water. For equilibrium b neither or H2 are suitable for describing the ionization occurring and a number of other methods have been used, e.g. the modified Marziano-Cimino-Passerini method, to obtain thermodynamic pKa values for the seven diarylsulphamides used in this study. The pKa values for equilibrium b are 15. The effect of substituents on both equilibria is similar. 

L. Passerini, and V. M. Goldschmidt and co-workers studied the solid soln. with alumina, and with ferric oxide q.v.). W. Muller said that the oxide prepared by reducing potassium chromate with dry—not moist—hydrogen chloride is quite different from the ordinary oxide, being greyish-green, composed of tube-like plates of the hardness of graphite. 

Monaco S, Arangio AM, Soavi F, Mastragostino M, Paillard E, Passerini S (2012) An electrochemical study of oxygen reduction in pyrrolidinium-based ionic liquids for lith-ium/oxygen batteries. Electrochim Acta 83 94—104... 

In studies summarized over two reports in 1920 and 1921, Mario Passerini described that the treatment of p-isonitrileazobenzene (6) with an acetone... 

Through further followup studies, Passerini expanded the scope of substrates to include a number of aldehydes and ketones as the carbonyl component and a variety of isonitriles including saturated alkyl isocyanides. Passerini also examined reactions where two components were combined into a single bifunctional substrate such as levulinic acid (8), where the carboxylic acid is proximally connected to a ketone. The reaction of levulinic acid with phenyl isocyanide gave amide 9 with the acyloxy moiety of the generic product now a y-lactone. ... 

The mechanism of Passerini reactions promoted by a Lewis acid has not been as extensively studied as the mechanism of the classic reaction. However, two precepts in regard to the component substitution should be noted. First, metal and metalloid-based Lewis acids are typically much more powerful acids than common carboxylic acids and second, as a consequence, nucleophiles (i.e., Lewis bases) will be both lower in strength and concentration under these conditions. Most of the differences in mechanism are inferred from indirect evidence, relying upon insight about the origins of observed products and side reactions, all of which logically proceed from a nitrilium intermediate. 

The Passerini reaction has also been utilized as a method for the homologation of heterocyclic carboxaldehydes. Studies by Weinreb and coworkers, directed toward the synthesis of amphimedine, have used a Passerini reaction for the homologation of the methoxypyridine derivative 65 with methyl isocyanide and acetic acid in methanol to give 66 in 77% yield. 

Schmuck M, Balducci A, Rupp B, Kent W, Passerini S, Winter M (2010) Alloying of electrodeposited silicon with lithium-a principal study of applicability as anode material for lithium ion batteries. J Solid State Electrochem 14 2203-2207... 

If in Chapter 7 different aspects about Ugi reaction have been discussed, in this chapter, we are going to disclose to the reader a vision about the new contributions regarding other crucial isonitrile-based multicomponent reaction (MCR) the Passerini reaction (P-3CR) discovered in 1921 [1], The traditional multicomponent Passerini reaction [2] is another isonitrile-based MCR that provides easy access to a-acyloxycarboxamides 4 in a one-pot synthesis involving an aldehyde 1, a carboxylic acid 2, and an isonitrile 3 (Scheme 8.1), which has been subject of intensive studies in the last decade [3], The importance of using isocyanides lays in its dual role as nucleophile and electrophile, and moreover, if R R, a new stereocenter could be created under asymmetric conditions. 

The mechanism of the Passerini reaction has been widely studied and the carboxylic acid 2 has been found to play a crucial role in the course of this process, where the activation of aldehyde 1 by the acid compound 2 would start the reaction as described in Scheme 8.2. Therefore, a carboxylic acid is normally required and it could represent a limitation for the applications of this process to the synthesis of more complex scaffolds. We disclose here some advances achieved in this field, in order to avoid the use of carboxylic acid and amplifying the scope of the process. 

The addition of simple salts such as NaOTs or Na SO to the aqueous phase provided an unusual variation of the selectivity of the Passerini-type MCR by shuttling the reactants between the two phases. This is an unusual fact since there are only few reports concerning the use of a salt showing a moderate effect on the ratio between isomeric products [59], but this study iuCTeases the possibilities for the development of new synthetic methodologies in aqueous media and using a Passerini methodology. The authors proposed a possible mechanism to explain the reactivity observed in each case and reflected in Schane 8.25. 

The results obtained in this study in terms of reaction time (Imin or less at 120°C) are remarkable as compared with our previous results on the Passerini reaction using, for instance, ionic liquids (2-14h) [61], PEG (0.5-6h) [61], CH Cl (18h) [57a], or water (3-3.5 h) [57a]. All these alternative solvents have been found to be efficient in this reaction, but in all cases, longer reaction times were required and lower yields were achieved. 

For a recent computational study, see S. Maeda, S. Komagawa, M. Uchiyama, K. Morokuma, Awgew. Chem. Int. Ed. 2011, 50, 644-649. Finding reaction pathways for multicomponent reactions the Passerini reaction is a four-component reaction. 

The Passerini synthesis is one of the oldest and most important multicomponent reactions (chronologically preceded by the reaction of Biginelli [1] and followed by the equally well-known Ugi four-component condensation reaction [2], currently widely studied for its originality in terms of application and mechanism). Surprisingly, little information is available regarding its discoverer, the Florentine chemist Mario Passerini. The reasons for the lack of a biography of this scientist can be traced, in part, to Passerini s reserved nature, reserved to the point of erroneously being perceived as shadowy. ... 

In October 1916, Guido Pellizzari became director of the Pharmaceutical Laboratories at the Instimtion of Higher Practical Studies and Specialization of Florence Passerini joined him there several years later. Passerini graduated in 1916, and was enrolled in 1920 as a Doctor of Philosophy student. His scholarship expired in 1924 the Chairman of the Advisory Council of the Institute arranged for him to become Pellizzari s research assistant. In this role, Passerini helped him mentor selected Ph.D. students. 

Blane CE, Zerin MJ, Bloom DA (1994) Bladder diverticula in children. Radiology 190 695-697 Blickman JG, Lehowitz RL (1984) The coexistence of primary megaureter and reflux. AJR 143 1053-1057 Blickman J, Taylor G, Lehowitz R (1985) VCU the initial study in children with UTL Radiology 156 659-662 Blyth B, Passerini-Glazel G, Camuffo C et al (1993) Endoscopic incision of ureteroceles intravesical versus ectopic. J Urol 149 556-559... 

The study by Mayo and Burns (1990) and the publication of Hoebeke et al. (1999) show that the number of cases with unstable bladder is around 60%. Passerini-Glazel et al. (1992) describe a rate of unstable bladder of 90% in children with nonneurogenic bladder-sphincter dysfunction. In 156 children with daytime incontinence, Van Gool (1992a) found unstable bladder in 53% and dysfunctional voiding in 59%. Weerasinghe and Malone (1993) reported unstable bladder in 54% and dysfunctional voiding in 3.5%. 

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