Enamine catalysis iminium compounds

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

In fact, this intramolecular version shortly preceded the intermolecular one discussed above, since the first example was disclosed by Kunz and MacMillan in 2005 [89], shortly followed by Jprgensen and co-workers [90]. This approach has proved to be highly versatile, leading to practical enantioselective syntheses of chiral cyclopropanes [89, 91], epoxides [90], and aziridines [92]. Finally, the use of bifunctional synthons in sequential iminium/enamine catalysis provides a very general entry to carbo- and heterocyclic compounds [93]. 

This study provided one of the first demonstrations [24] that chiral secondary amines can integrate orthogonal activation modes of carbonyl compounds (enamine and iminium ion catalysis) into more elaborate reaction sequences, catalyzing more than one stereocontroUed bond-forming event As detailed in Section 42.2.2, this concept greatly permeated and boosted future developments in the field of asymmetric organocatalytic MCRs. 

L-Proline is perhaps the most well-known organocatalyst. Although the natural L-form is normally used, proline is available in both enantiomeric forms [57], this being somewhat of an asset when compared to enzymatic catalysis [58], Proline is the only natural amino acid to exhibit genuine secondary amine functionality thus, the nitrogen atom has a higher p Ka than other amino acids and so features an enhanced nucleophilicity compared to the other amino acids. Hence, proline is able to act as a nucleophile, in particular with carbonyl compounds or Michael acceptors, to form either an iminium ion or enamine. In these reactions, the carboxylic function of the amino acid acts as a Bronsted acid, rendering the proline a bifunctional catalyst. 

The rates of hydrolysis of compounds 12 (X = H), 13 and 14 are independent of pH from about pH 6 to 1, and buffer catalysis is not seen. The interpretation of these results is the same as it is for series 5, namely rate-controlling attack by water on the iminium ion. At these pH values the enamine is present in a protonated form and equation 23 is the rate law. As is clear from Figure 2, the morpholine-derived iminium ion is by far the most electrophilic, while the pyrrolidino iminium ion is least reactive. This order is exactly the same as for compounds 1-3 the reasons were discussed in Section III.A.2. Rate constants for nucleophilic attack upon the iminium ions are given in Table 8. 

It is possible that conjugated enamines such as enaminones hydrolyze by the mechanism shown in Scheme 2, a variation of Scheme 1 in which nucleophilic hydration occurs on an O-protonated enamine rather than on the C-protonated (iminium) ion. This mechanism has been proposed for the acidic hydrolysis of compounds 36 and 37. This mechanism cannot be considered established, however, as the experiments that would rule out C-protonation were not done. It is highly pertinent that hydrolyses of other conjugated enamines, 10,11, 25, 26,39 and 40, all obey the expectations of Scheme 1, equation 15, namely they exhibit general-acid catalysis and (for 25, 26, 39 and 40) primary kinetic solvent isotope effects. 

Proline is a stable, nontoxic, cyclic, secondary pyrrolidine-based amino acid with an increased pK value. Thus, proline is a chiral bidentate compound that can form catalytically active metal complexes (Melchiorre et al. 2008). Bidentate means that proline has not only one tooth but also a second one to bite and react. The greatest difference to other amino acids is a Lewis-base type catalysis that facilitates iminium and enamine-based reactions. It is especially noteworthy that cross-aldol condensations of unprotected glycoladehyde and racemic glyceralde-hyde in the presence of catalytic amounts of the Zn-(proline)2 gave a mixture of pentoses and hexoses (Kofoed et al. 2004). Again, proline seems to play the decisive role. The conditions are prebiotic the reaction proceeded in water for seven days at room temperature. It is remarkable that the pentose products contained ribose (34%), lyxose (32%), arabinose (21%), and xylose (12%) and that all are stable under the conditions. Thus, the diastereomeric and enantiomeric selection observed support the idea that amino acids have been the source of chirality for prebiotic sugar synthesis. 

L-Proline could be used as an effective catalyst via dual-enamine-iminium-catalysis modes. Pyrrolidine was ineffective, indicative of the crucial role of proline s carboigrlate moiety. The Meldrum s acid derivatives could be postfunctionalised via methanolysis and in situ decarboig lation to produce complex 1,5-dicarbonyl compounds. This strategy was applied towards the synthesis of polycyclic chromene derivatives (38, Scheme 5.43). ... 

Even though the use of (S)-proline (1) for the synthesis of the Wieland-Miescher ketone, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaetion, was reported in the early 1970s, aminocatalysis - namely the catalysis promoted by the use of chiral second-aiy amines - was rediscovered only thirty years later. The renaissance of aminocatalysis was prompted by two independent reports by List et al. on the asymmetric intermolecular aldol addition catalysed by (S)-proline (1) and by MacMillan et al. on the asymmetric Diels-Alder cycloaddition catalj ed by a phenylalanine-derived imidazolidinone 2. These two reactions represented the archetypical examples of asymmetric carbonyl compound activation, via enamine (Figure ll.lA) and iminium-ion (Figure 11.IB), respectively. 

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