Pyrrolidinodiones in Enol-Ugi, Enol-Passerini and anomalous enol-Passerini condensations

In continuation of our recent research on the development of novel multicomponent reactions with isocyanides, we have used, for the first time, enols as the acid components in Ugi- and Passerini-type reactions. Thus, electron-poor pyrrolidinodiones react with aldehydes, amines, and isocyanides to give the enaminic four-component adducts. Conversely, in the absence of the amine component, careful control of the reaction conditions allows the involvement of one or two molecules of isocyanide to afford, selectively, either Passerini-type or pseudo-enol-Ugi-type products. These unprecedented condensations of isocyanides, aldehydes, amines, and 4-substituted pyrrolidine-2,3-diones constitute an excellent strategy for the preparation of new biologically relevant pyrrolidinones having peptidic or pseudo-peptidic groups on carbon 3.


Enol-Ugi Condensations
Enolic pyrrolidine-2,3-diones (1), imines (2), and isocyanides (3) were mixed in methanol at room temperature to give the expected Ugi-type adducts (4, Scheme 2), which were isolated in very good to excellent yields. They were identified according to their spectral data, and the structure was further confirmed by X-ray diffraction analysis ( Figure 2) [35].  The reaction shows a wide scope and has been performed with different combinations of imines, isocyanides, and pyrrolidinodiones ( Figure 3). We have also shown that it is possible to form the imines in situ from the corresponding amines and aldehydes; thus, the four-component condensation can be accomplished.  The mechanism of the reaction can be explained by the protonation of the imine to form an iminium cation, which is attacked by the isocyanide to give a nitrilium cation intermediate. This then suffers the nucleophilic attack of the enolate, resulting in a primary adduct analogous to the primary adduct in the classical Ugi condensation. Thus, up to here, the reaction is mechanistically similar to the Ugi condensation with carboxylic acids. However, in the enol-Ugi condensation, the primary adducts spontaneously evolve to a stable product by a Michael-retro-Michael rearrangement, instead of the Mumm rearrangement that takes place in the classic U-4CC (Scheme 3).

Scheme 3.
Possible mechanism of the enol-Ugi condensation.

Enol-Passerini Condensations
In this case, the reaction was performed by mixing enolic pyrrolidine-2,3-diones (1), aldehydes (5), and isocyanides (3). The reaction takes place optimally at room temperature in dichloromethane, readily affording the corresponding pyrrolidinone amido ethers (6) in good to excellent yields [32]. The reaction is also possible in on-water conditions (i.e., using water as the solvent (Scheme 4)). The reaction has been also shown to be quite general, allowing the use of diverse aromatic aldehydes, pyrrolidinodiones, and both aliphatic and aromatic isocyanides (Figure 4). A mechanism in which the pyrrolidinodione acts as the acid component of the condensation can be envisaged. In parallel with the classical Passerini condensation, the reaction purportedly takes place in a concerted manner, as show in Scheme 5.

Scheme 5.
Possible mechanism of the enol-Passerini condensation.

Anomalous Enol-Passerini Condensations
Finally, the reaction of pyrrolidine-2,3-diones (1), aldehydes (5), and two equivalents of isocyanides (3) in polar solvents, such as methanol, yielded a pseudo-enol-Ugi four-component adduct (7; Scheme 6) [32]. In this case, the reaction admits diverse aldehydes and pyrrolidinodiones, but it is not possible with bulky isocyanides ( Figure 5). The mechanism can be rationalized considering that a [2+2] cycloaddition of an aldehyde and a protonated isocyanide, followed by the cycloreversion and transfer of a formyl group to the solvent to give methyl formate and an intermediate iminium ion. This can then participate in a subsequent enol-Ugi reaction (Scheme 7). It had been previously observed that isocyanides and aldehydes can react to give imines in the presence of Bronsted [36] or Lewis acids [37].

Conclusions
In summary, we have used enols for the first time as the acid component in Ugi-and Passerini-type reactions. Careful control of the reaction conditions allows us to obtain Ugi, Passerini, or pseudo-enol-Ugi products selectively. The use of enols as acidic partners in MCRI is an excellent strategy for the preparation of new pyrrolidinones having peptidic or pseudo-peptidic groups on carbon 3.