Enamine activation reactions

As it happened in enamine activation reactions, the most remarkable feature of this strategy is the high atom efficiency of the process and also the operational simplicity of the experimental protocol, because of the compatibility of the reagents and intermediates participating in the reaction toward the presence... 

The most characteristic reaction of butadiene catalyzed by palladium catalysts is the dimerization with incorporation of various nucleophiles [Eq. (11)]. The main product of this telomerization reaction is the 8-substituted 1,6-octadiene, 17. Also, 3-substituted 1,7-octadiene, 18, is formed as a minor product. So far, the following nucleophiles are known to react with butadiene to form corresponding telomers water, carboxylic acids, primary and secondary alcohols, phenols, ammonia, primary and secondary amines, enamines, active methylene compounds activated by two electron-attracting groups, and nitroalkanes. Some of these nucleophiles are known to react oxidatively with simple olefins in the presence of Pd2+ salts. Carbon monoxide and hydrosilanes also take part in the telomerization. The telomerization reactions are surveyed based on the classification by the nucleophiles. 

The preparation of dithianes from enamines by reaction with trimethylene dithiotosylate (propane-1,3-dithiol di-p-toluenesulfonate) has been applied with enamines derived from oholostan 3 one, aceto-acetic ester, and phenylacetone.6 7 Reactions of trimethylene dithiotosylate with hydroxymethylene derivatives of ketones also give rise to dithianes thus the hydroxymethylene derivative of cholest-4-en-3-one can be converted to 2,2-(trimethylenedithio)cholest-4-en-3-one. 1,3-Dithiolanes are obtained in a similar manner by reaction of ethylene dithiotosylate1 with the appropriately activated substrate.5,7... 

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],... 

Direct metalation at the /8-carbon of azoles can also occur, although it is a much less facile process than that for the adjacent a-carbon, because of the greater charge density at what is normally a nucleophilic center in enamine-type reactions. Thus in order for reaction to occur, it is usually necessary to either block the a-position or activate the /3-site. If both factors are accommodated than /8-metalation occurs readily, and thus 3,4-disubstituted-2(3//)-thiazolethiones undergo direct lithiation with lithium diisopropylamide (LDA) at the 5-position, which is activated by the inductive effect of the adjacent sulfur (Scheme 4) (80S800). 

Although the direct reaction of a lipoyl group with the thiamin-bound enamine (active aldehyde) is generally accepted, and is supported by recent studies,3153 an alternative must be considered.315 Hexacyanoferrate (III) can replace NAD+ as an oxidant for pyruvate dehydrogenase and is also able to oxidize nonenzymatically thiamin-bound active acetaldehyde... 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

The most commonly used type of catalyst is a relatively small, bifunctional molecule that contains both a Lewis base and a Bronsted acid center, the catalytic properties being based on the activation of both the donor and the acceptor of the substrates. The majority of organocatalysts are chiral amines, e.g. amino acids or peptides. The acceleration of the reaction is either based on a charge-activated reaction (formation of an imminium ion 4), or involves the generalized enamine catalytic cycle (formation of an enamine 5). In an imminium ion, the electrophilicity compared to a keton or an oxo-Michael system is increased. If the imminium ion is deprotonated to form an enamine species, the nucleophilicity of the a-carbon is increased by the electron-donating properties of the nitrogen. ... 

Reaction with enamines. The reaction of dibenzoyl peroxide with an enamine provides an indirect way of introducing a benzoyloxy group into an active methylene compound, such as (1). ... 

This asymmetric Mannich reaction could also proceed by an enamine pathway because nucleophilic addition of the in situ-generated enamine would be faster to an imine than to an aldehyde. As shown in the Fig. 12.59, the reaction starts with enamine 34 activation of the cyclohexanone by the proline anion and an electrostatic interaction with the imidazolium moiety of the catalyst In a second pre-equilibrium, the aldehyde and aniline produce an imine. Then enamine-activated 35 reacts with the imine to form 35 via transition state A. The last step is a dehydration reaction to afford the corresponding product. The catalyst is regenerated in the subsequent step. 

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. 

The high activating power of NR2 groups allows substituent effects in enamines in reactions with... 

Enantioselective Conjugate Addition Reactions via Enamine Activation... 

The foundations of this concept (enamine activation) lie in the fundamental studies by Stork and Robinson covering the stoichiometric use of enamine nucleophiles for the formation of C-C bonds. The Hajos-Parrish-Eder-Sauer-Wiechert reaction reported in 1971 (Scheme 2.2), which consisted of a... 

Scheme 2.3 Proposed mechanistic models for the Michael reaction under enamine activation.

As has already been mentioned, the low reactivity of enamine nucleophiles needs a highly electrophilic Michael acceptor for the reaction to proceed with good conversions in an acceptable time. In this context, the Michael reaction of aldehydes and ketones with nitroalkenes can be regarded as one of the most studied transformations in which the enamine activation concept has been applied. This reaction furnishes highly functionalized adducts with remarkable potential in organic synthesis, due to the synthetic versatility of the nitro group and the presence of the carbonyl moiety from the donor reagent. 

Nevertheless, as was pointed out before, a straightforward solution to the rather limited substrate scope of the reaction with regard to the ketone reagent and also a good way to overcome the lack of reactivity of ketones toward enamine activation has been the use of primary amines as organocatalysts. In fact, literature examples indicate that primary amines are much more active catalysts for the Michael addition of both cyclic and acyclic ketones to nitroalkenes compared to the same reaction using a secondary amine catalyst like most of the proline-based derivatives already presented before. 

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