Mechanisms enamine/iminium

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

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. ... 

Isomerisation studies indicate that the iminium ion formed initially prior to isomerisation as the amount of ( ) product increased over time. Only the (Z) isomer was observed after 10 min. Notably, nonenolisable aldehydes i.e. acrylaldehyde and cinnamaldehyde) were unreactive, indicative of an enamine-type mechanism as opposed to a typical aza-MBH route. Several procedures for the asymmetric, proline-catalysed MBH reaction between methyl vinyl ketone (MVK) and aromatic aldehydes have been developed to date. ... 

Shortly later, within 2 months, a similar reaction, the enantioselective cascade aza-ene-type cyclization reactions of a,p-unsaturated aldehydes 28 and enamide 154, was also reported by Wang et al. In addition, the reaction product hemiaminal 157 was converted to ketoaldehyde 158, pyridine 159 and enamide 160, Scheme 3.51 [67]. Similarity, the reaction mechanism started from a nucleophilic attack of enamide (an aza-ene-type reaction), followed by reversible enamine-iminium transformation and hydrolysis to provide the hemiaminal. 

As mentioned, the applications of chiral secondary amines in domino processes have been numerous, mainly because of the dual mechanism of activation allowing easy incorporation of other reactions [7, 8]. The first of these processes involves an iminium-enarnine (Scheme 7.1a), and the second an enamine-iminium activation (Scheme 7.1b), both of which can be in operation in domino reactions involving Michael reactions. These modes of action rely on the lower energy lowest unoccupied molecular orbital (LUMO) for the iminium ion and a rise in the highest occupied molecular orbital (HOMO) energy for enamine activation, which are discussed in further detail in Chapter 10 of this book [9, 10]. In the... 

Scheme 10.2 Mechanism of enamine-iminium activation mode.

The direct asymmetric aldol reaction is a powerful tool for C-C bond formation. Enamine-iminium catalysis is the most developed, and it is nicely complimented by other modes of activation that rely on hydrogen bond formation. Mechanistically, all proline-based catalysts activate donors through the formation of an enamine intermediate. Other activation modes rely on enolate formation, ionic interactions, or hydrogen bond formation, though the mechanism is not always known. 

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. 

Scheme 2.7 Asymmetric reductive Michael cyclization and schematic representation of the tandem iminium-enamine catalysis mechanism...

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. 

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. 

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. 

Hong and co-workers have described a formal [3-t-3] cycloaddition of a,P-unsaturated aldehydes using L-proline as the catalyst (Scheme 72) [225], Although the precise mechanism of this reaction is unclear a plausible explanation involves both iminium ion and enamine activation of the substrates and was exploited in the asymmetric synthesis of (-)-isopulegol hydrate 180 and (-)-cubebaol 181. This strategy has also been extended to the trimerisation of acrolein in the synthesis of montiporyne F [226],... 

Whereas the examples discussed so far proceed according to the iminium ion mechanism (A), amine-catalyzed additions of, e.g., ketones to nitroolefins are effected by intermediate enamine formation (B). List et al. were the first to report that L-proline catalyzes the addition of several ketones to nitroolefins (Scheme 4.23). Whereas both the yields and diastereoselectivity were high in DMSO as solvent, the ee did not exceed 23% [38]. A related study of this process by Enders and Seki resulted in identification of methanol as a superior solvent, and enantioselec-tivity up to 76% was achieved (Scheme 4.23) [39]. 

The Willgerodt Reaction allows the synthesis of amides from aryl ketones under the influence of a secondary amine and a thiating agent. The mechanism involves the formation of an enamine which undergoes thiation, and the carbonyl group migrates to the end of the chain via a cascade of thio-substituted iminium-aziridinium rearrangements. 

The scope and mechanism of ionic hydrogenation of iminium cations have been investigated for a CpRuH catalyst bearing a chelating diphosphine.64 The mechanism involves three steps hydride transfer (from the catalyst) to form an amine, coordination of H2 to the resulting ruthenium cation, followed by proton transfer from the dicoordinated H2 to the amine. The cationic intermediate [e.g. CpRu(dppm)( 72-H2)+] can be used to hydrogenate enamines provided that the latter are more basic than the product amine. The relative reactivity of C=C and C=N bonds in a, ft -unsaturated iminium cations has also been investigated. 

Diphenylpyrrolidine (77) catalyses the enantioselective cy-chlorination of aldehydes.299 Mechanistic and computational studies suggest that - in contrast to pre- viously proposed mechanisms involving direct formation of the carbon-electrophile bond - iV-chlorination occurs first, followed by a 1,3-sigmatropic shift of chlorine to the enamine carbon. The product iminium ion is then hydrolysed in the ratedetermining step. 

The mechanism of the thermal decomposition of NMMO and Lyocell solutions is extremely complex since the reaction, initiated by the action of carbenium-iminium ions, quickly enters an uncontrollable course. A central question was whether the heterocyclic ring of NMMO was cleaved during the reaction and whether products of this cleavage, having either vinyl ether or enamine structures, could be detected. Employing the trapping agents... 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

The reaction of an aldehyde or a ketone with a secondary amine follows exactly the same mechanism as the reaction with a primary amine (see Figure 18.3) until the final step. Unlike the case with a primary amine, the nitrogen of the iminium ion does not have a proton that can be removed to produce a stable imine. Therefore, a proton is removed from an adjacent carbon, resulting in the formation of an enamine. Enamine formation is illustrated in the following equations. In each case the equilibrium is driven toward the products by removal of water. 

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