Carbonyl compounds, Passerini reaction

Modern MCRs that involve isocyanides as starting materials are by far the most versatile reactions in terms of available scaffolds and numbers of accessible compounds. The oldest among these, the three-component Passerini MCR (P-3CR), involves the reaction between an aldehyde 9-1, an acid 9-2, and an isocyanide 9-3 to yield a-acyloxycarboxamides 9-6 in one step [8], The reaction mechanism has long been a point of debate, but a present-day generally accepted rational assumption for the observed products and byproducts is presented in Scheme 9.1. The reaction starts with the formation of adduct 9-4 by interaction of the carbonyl compound 9-1 and the acid 9-2. This is immediately followed by an addition of the oxygen of the carboxylic acid moiety to the carbon of the isocyanide 9-3 and addition of this carbon to the aldehyde group, as depicted in TS 9-5 to give 9-5. The final product 9-6 is... 

In this period, the most important reactions of the isocyanides were the formations of tetrazole derivatives from isocyanides and hydrazoic acid, a process introduced in 1910 by Oliveri-Mandala and Alagna, and then in 1921 Passerini introduced the reaction (P-3CR), which was the first 3-component reaction of the isocyanides. In the 1940s Baker,and later Dewar, proposed mechanisms of the P-3CR. The important role of the intermediate hydrogen bond between the carboxylic acid and the carbonyl compound in suitable solvents was mentioned. ... 

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. 

In the classical Passerini reaction [11], an isocyanide is condensed with a carbonyl compound and a carboxylic acid to afford a-acyloxyamides 7 (Scheme 1.2). When the carbonyl compound is prochiral, a new stereogenic center is generated. It is generally accepted that the reaction proceeds through intermediate 6, which rearranges to the product. The way this intermediate is formed is more debated. A possibility is a concerted non-ionic mechanism involving transition state 5. Since the simultaneous union of three molecules is not a very likely process, another possibility is a stepwise mechanism, with the intermediacy of a loosely bonded adduct 4 between the carbonyl compound and the carboxylic acid [2], Since all three... 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

In most cases chiral carbonyl compounds also afford low stereoselectivity. As for the related Passerini reaction, even the use of aldehydes that are known to give excellent asymmetric induction in the reaction with other kinds of C-nucleophiles, results in low or moderate diastereoisomeric ratios. For example, both norbornyl aldehyde 39 [47] and a-alkoxyaldehyde 40 [3, 48] gave drs lower than 2 1 (Scheme 1.16). The same happens with ortho-substituted chromium complex 41 [49], which usually leads to very high asymmetric induction in other nucleophilic additions. Finally, //-substituted aldehyde 42 [50] gave poor results as well. 

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

The mechanism of the Passerini reaction was widely examined. A plausible mechanism that is consistent with experimental data is as follows First, the carbonyl compound and the carboxylic acid forms a hydrogen bonded adduct. Subsequently, the carbon atom of the isocyanide group attacks the electrophilic carbonyl carbon, and also reacts with the nucleophilic oxygen atom of the carboxylic acid. The resulting intermediate cannot be isolated as it rearranges to the more stable a-acyloxycarboxamide in an intramolecular transacylation. 

Passerini multicomponent reaction Condensation of isocyanides with carboxylic acids and carbonyl compounds to afford a-acyloxycarboxamides. 330... 

The Passerini reaction, also called the 3-CC reaction, which consists of the reaction of a carboxylic acid, a carbonyl compound, and an isocyanide providing an a-(acyloxy)carboxamide in a single step, was carried out for the first time in [bmim] [BFJ (Fig. 12.1) [1]. 

Between 1921 and 1931,Passerini introduced and investigated the reaction which bears his name [8-10], forming the products 16 from carbonyl compounds 1, carboxylic acids 3A and isocyanides 13. The discovery of the P-3CR was a milestone in the development of isocyanide-based MCRs, as it was the introduction of the first practicably irreversible MCR of these compounds. 

Carbonyl compounds and imines are the electrophilic partner of isocyanides in the Passerini-3CR and the Ugi-4CR, respectively. Other highly electrophilic multiple bonds, such as in dimethyl acetylenedicarboxylate (DMAD), are also known to react with isocyanides. The initially formed 1 1 zwitterionic species having carbanion, carbene character can undergo further reaction with DMAD and isocyanides in different molar ratios, leading to a variety of heterocyclic systems (Scheme 5.32) [69]. 

In 1921 Passerini reported the synthesis of the a-acyloxycarboxamides (6a-e) according to the scheme below. The formation of a-acyloxycarboxamides by a three-component reaction of carboxylic acids (3), carbonyl compounds (4) and isocyanides (5) is the proper Passerini reaction. The reactions described in Sections 4.6.2.2-4.6.2.4 are closely related to the Passerini reaction we call them reactions of the Passerini type. ... 

The Passerini reaction of a-halogenated carbonyl compounds (8 X = Cl, Br) can be used for the protection of the C-terminal carboxyl groups of A -protected a-amino acid derivatives (7). ... 

Accordingly, the Ugi reaction is closely related to the Mannich reaction and may be classified as an a-aminoalkylation. However, at the same time, a special type of Ugi reaction, the formation of a-acylami-nocarboxamides (42g) by 4CC of carboxylic acids and primary amines with carbonyl compounds and isocyanides, resembles the Passerini reaction (see Section 4.6.2). 

The Passerini reaction and the formation of a-hydroxycarboxamides (24) may compete with the Ugi reaction. When carboxylic acids (3) and carbonyl compounds (4) with electron-withdrawing groups are subjected to 4CC in nonpolar solvents such as dichloromethane, the Passerini reaction may compete strongly. Also, with bulky components the Passerini reaction becomes a serious side reaction of the Ugi reaction. ... 

Solution The Passerini reaction involves the combination of a carbonyl compound with a carboxylic acid and an iso-... 

Other reactions, in which carbenium ion addition to an isocyanide is the key step, are the Passerini and Ugi reactions and reactions of similar type. These multicomponent transformations have recently been reviewed The Passerini reaction starts from an isocyanide, a carbonyl compound and a carboxylic acid. 

The condensation of a carbonyl compound with an isonitrile usually takes place in the presence of a carboxylic acid to give carboxamides (Passerini reaction) and plays a central role in combinatorial chemistry. Activation of the carbonyl group can be achieved by TMSOTf (eq 58), although higher yields can be obtained with the system Zn(OTf)2/TMSCl. ... 

Initially, Passerini proposed that the reaction involved an addition of carboxylic acid to carbonyl compound, giving acyloxy hemiacetal, which then reacted with isonitrile to form the final product. However, current views about this reaction favor the following consecutive processes the protonation of the carbonyl compound from carboxylic acid, followed by the attack of isonitrile to give a nitrilium ion, the nucleophilic addition of carboxylate, acyl group transfer, and the final amide tautomerization. A general mechanism for this reaction is shown here. ... 

The Passerini reaction is normally a sluggish reaction, often performed over several days. Therefore, an important consideration is the relatively low reactivity of the component substrates. Electronic or steric elements that might further retard the reaction rate will predictably give lower yields and substantially more side products. Conversely, more reactive carbonyl compounds such as chloral can be attacked by isonitriles and form a-hydroxyamides even in the absence of an acid component. 

In this context, Zhu and coworkers envisioned the great utility of alcohols in Passerini reaction instead of aldehydes, which are unstable and sometimes difficult to handle, since the carbonyl compounds can be obtained by direct oxidation of the corresponding alcohols. Thus, the authors generated in situ the aldehydes by oxidation of the alcohols 29 using IBX to obtain a-acyloxycarboxamide derivatives 30 in good yields (Scheme 8.10) [22]. 

In 1921, he published his first paper on what would later be called the Passerini reaction. This three-component reaction, a carboxylic acid, a carbonyl compound (such as a ketone or an aldehyde) and isocyanides, opened the way for direct synthesis of hydroxylated carboxamide. 

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