Passerini reaction mechanism

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. The following mechanism has been postulated ... 

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 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... 

Since the Passerini reaction is accelerated in aprotic solvents, it is assumed that the reaction follows a nonionic pathway. The most plausible mechanism of the reaction is depicted in Scheme 2 ([25] and see for review [26] [13]). 

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. 

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. 

In the 1940s, Baker and Linn [41], and later Dewar [42], each 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. The most plausible mechanism of the Passerini reaction is depicted in Scheme 4.2 (1 + 3A + 13 -> 16) [43]. 

Based on this evidence, the reaction mechanism (22) + (5) - (23) - (6) is the most convincing of the many proposed reaction mechanisms for the Passerini reaction.2)... 

The generally accepted mechanism for the Passerini reaction is illustrated by aldehyde 10 (or ketone) being activated for nucleophilic addition by complexation with carboxylic acid 11. The precise nature of this complex is has not been established, however, Ugi has favored the internally hydrogen... 

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. 

For a brief period of time it was thought that the TiCU-promoted Passerini reaction occurred via a mechanism where a nitrilium adduct did not play any significant role. This thinking was based on some initial evidence that isonitriles inserted into Ti-Cl bonds and formed titanium imidochlorides and that these species were incorporated into the mechanism as intermediates. However, subsequent FT-IR and X-ray crystal structure data strongly suggested that isonitriles do not insert into... 

Most attempts to construct diastereoselective variants of the Passerini reaction have met with a certain degree of failure. Undoubtedly, the numerous uncertainties of the reaction mechanism have contributed to these difficulties. The usual low levels of control for the Passerini reaction have also impeded efforts to establish empirical trends in the diastereofacial selectivity. This is exemplified in the construction of peptidomimetics, a class of molecules which has stimulated numerous applications of the Passerini reaction, where the diastereoselectivity is typically in the range of 1 1 to 4 1, A survey of results of the diastereofacial selectivity of carbonyl addition does not consistently follow a clear trend of either the Felkin-Anh or chelation-controlled models of carbonyl addition. ... 

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. 

On the basis of these results and additional control experiments, the authors proposed a plausible mechanism to explain the 0-silylative Passerini reaction as depicted in Scheme 8.8. 

Subsequently Passerini tried to determine the reaction mechanism for this new type of reaction. At first, he proposed a trimolecular process but, shortly afterward, he was inclined to propose a different mechanism, more consistent with traditional rules of organic chemistry. This mechanism would have proceeded through a non-isolable intermediate, generated by addition of the ketone to the acid, which would have, finally, reacted with isocyanides. 

It was only two years later that Passerini had an opportunity to return to this, his work he published two additional notes, more extensive and containing more details. He added, however, very little novel material he noted that the subclass of cyclic ketones were well-suited for multi-component reactions. His fourth and final note on the Passerini reaction was published in March 1924 [9]. In this work, Passerini unequivocally demonstrated that his reaction was a general reaction involving isocyanides, and aromatic aldehydes or ketones, in the presence of organic acids. Passerini regretted that, still examining the reaction mechanism, based on intermediate formation, he had failed to isolate it, although he referred to unspecified chemical and physical experiments by which he hoped to ascertain its existence. ... 

This organic reaction is the first multi-component reaction based on isocyanides it currently plays a central role in combinatorial chemistry. Recently S. E. Denmark and Y. Fans have developed an enantioselective catalyst for asymmetric Passerini reactions, whose reaction mechanism is not well understood even to this day [12]. 

In non-polar solvents and at high concentration, a concerted mechanism is hypothesized [13]. This mechanism involves a tri-molecular reaction among the isocyanide, the carboxylic acid, and the carbonyl in a sequence of nucleophilic additions. The transition state (below) is depicted as a 5-memhered ring with partial covalent or double bonding. The second step of the Passerini reaction is an acyl transfer to the neighboring hydroxyl group, 2. There is support for this proposed... 

Scheme 1 The Passerini-3CR involving carboxylic acid, aldehyde, and isocyanide (/ ) and the Ugi-4CR with additional primary amine (right). The respective reaction mechanisms are depicted...

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