Iminium mechanism

Scheme 15 Double activation of reaction components by an enamine/iminium mechanism [81]...

As noted above, many decarboxylases are known to exploit Schiff base formation in the active-site as a source of catalysis. Shostack and Jones explored this possibility in the case of ODCase [8]. They found that when the enzymatic reaction is performed in 0 water, the product does not incorporate from bulk solvent. For this reason, a covalent iminium mechanism for ODCase was abandoned, in spite of its attractive similarities to other decarboxylase mechanisms. 

Scheme 3 Chiral imidazolium salt-catalyzed Diels-AIder reaction proceeding via an iminium mechanism (27)...

The enantioselective Michael addition of malononitrile CH2(CN)2 to trans-chalcones R CH=CHCOR catalysed by diarylprolinols (151), has been studied in detail. Both experimental and computational results are consistent with a bifunctional non-covalent activation of the reactants (152). The latter mechanism correctly predicts formation of the (R)-configured products (<75% eef- but is in conflict with the generally accepted iminium mechanism. Furthermore, (151) is likely to form the corresponding oxazolidine derivative as an intermediate, which has not been taken into account. 

The vinylogous functionalization of enones and enals, using primary and secondary amines RR NH as catalysts, featuring the enamine/iminium mechanism, has been discussed in the enamine subchapter. ... 

Three main mechanisms have been proposed for the Biginelli reaction. In 1933, Folkers and Johnson proposed three potential key intermediates (5-7) involved in the Biginelli reaction (Figure 3) [6]. Intermediate 5 could be formed via an iminium mechanism from the condensation of aldehyde and urea. Intermediate 6 may be formed via an enamine mechanism from the condensation of urea and 1,3-dicarbonyl compoxmd. The third option involves intermediate 7, which can be formed via a Knoevenagel condensation of an aldehyde and a 1,3-dicarbonyl compound. Folkers and Johnson believed that intermediate 5 was preferentially formed over 6 or 7. 

In 2012, Ramos and collaborators also studied this mechanistic pathway by means of ESI-MS, NMR, and theoretical calculations in their approach [9]. In this work, the mechanism of the Biginelli reaction was explored by studying the influence of Lewis acid catalysts in the presence of ionic liquids. Once again, the researchers noticed the exclusive formation of iminium intermediate m/z 149 (Figure 4), indicating that xmder Lewis Acid catalysis and in ionic liquids, the preferred mechanistic pathway was the iminium mechanism [9]. 

Thus, through the experimental evidence obtained both by Kappe, de Souza and collaborators, and by Ramos and colleagues, we can verify the preference for the iminium mechanism as proposed initially by Folkers and Johnson [6]. 

The reaction has been applied to more complex enamines 13) and to dienamines 19). The reduction may be rationalized by initial protonation at the enamine carbon and subsequent decarboxylation of formate ion and addition of the hydride ion to the iminium cation. This mechanism has been given support by the reaction of the enamine (205) with deuterated formic acid 143) to give the corresponding amines. The formation of 206 on reaction with DCOOH clearly indicates that protonation at the enamine carbon is the initial step. 

The reduction of iminium salts can be achieved by a variety of methods. Some of the methods have been studied primarily on quaternary salts of aromatic bases, but the results can be extrapolated to simple iminium salts in most cases. The reagents available for reduction of iminium salts are sodium amalgam (52), sodium hydrosulfite (5i), potassium borohydride (54,55), sodium borohydride (56,57), lithium aluminum hydride (5 ), formic acid (59-63), H, and platinum oxide (47). The scope and mechanism of reduction of nitrogen heterocycles with complex metal hydrides has been recently reviewed (5,64), and will be presented here only briefly. 

In the case of unsubstituted BFO 1 reacting with an enamine, the following mechanism is generally accepted in the literature. The first step is nucleophilic addition of an enamine 2 to electrophilic BFO 1 to form the intermediate 12. Ring closure occurs via condensation of the imino-oxide onto the iminium functionality to give 13. Finally, P-elimination of the dialkyl amine produces the quinoxaline-1,4-dioxide 4. 

The mechanism was then reexamined 25 years later in 1997 by Kappe. Kappe used H and C spectroscopy to support the argument that the key intermediate in the Biginelli reaction was iminium species 16. In the event, 5 reacted with 3a to form an intermediate hemiaminal 17 which subsequently dehydrated to deliver 16. Iminium cation 16 then reacted with 6 to give 14, which underwent facile cyclodehydration to give 15. Kappe also noted that in the absence of 6, bisureide 8 was afforded as a consequence of nueleophilic attack of 16 by urea (3a). This discovery confirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal from 25 years earlier by Sweet and Fissekis, Kappe saw no evidenee by H and NMR spectroscopy that a carbenium ion was a required species in the Biginelli reaetion. When benzaldehyde (5) and ethyl... 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

Another mechanism has been formulated, which is based on results obtained by Knoevenagel, and which is supported by more recent investigations. It involves the formation of an intermediate iminium species 7 ... 

There have been extensive investigations on the reaction mechanism. In most cases the reaction proceeds via initial nucleophilic addition of ammonia 2 to formaldehyde 1 to give adduct 5, which is converted into an iminium ion species 6 (note that a resonance structure—an aminocarbenium ion can be formulated) through protonation and subsequent loss of water. The iminium ion species 6 then reacts with the enol 7 of the CH-acidic substrate by overall loss of a proton ... 

Mechanism of enamine formation by reaction of an aldehyde or ketone with a secondary amine, R2NH. The iminium ion intermediate has no hydrogen attached to N and so must lose H+ from the carbon two atoms away. 

On the other hand, the known facts point to an alternative interpretation. The stereochemical course of the reaction may be explained in terms of a polar [2s + 2s] cycloaddition15 which is observed in reactions between very electron-poor and very electron-rich alkcnes. Namely, polar [2 + 2] cycloadditions usually proceed with high regioselectivity ( head to head ) and stereoselectivity under mild conditions33 35. This mechanism is also supported by the fact that a closely related reaction (between an ynamine and iminium salts) passes through a cyclic 4-membered intermediate36, which is probably the result of a polar [2 + 2] cycloaddition (see refs 10 and 37). 

Eq. 25) [295]. A similar mechanism has also been proposed for the electrolysis of isobutyric and pivalib acid in acetonitrile [296]. As the intermediate alkyl cation can rearrange and the intermediate iminium cation can furthermore react with the starting carboxylic acid three different amides can be isolated (Eq. 26) [295 a]. The portion of the diacylamide can be considerably increased if the electrolyte consists of acetonitrile/ acetic acid [295 b]. 

According to this mechanism, it is the free amine, not the salt that reacts, even in acid solution and the active-hydrogen compound (in the acid-catalyzed process) reacts as the enol when that is possible. This latter step is similar to what happens in 12-4. There is kinetic evidence for the intermediacy of the iminium ion (13). 

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