Carbonyl compounds, addition reactions enamine formation

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Enamine formation, like many other carbonyl addition reactions, is readily reversible, and the carbonyl compound can be recovered by hydrolysis with aqueous acids. For this reason, to obtain a good conversion of carbonyl compound to enamine, it usually is necessary to remove the water that is formed by distilling it away from the reaction mixture. 

Small chiral organic molecules may catalyze the asymmetric addition of ketones, and aldehydes to electron-deficient olefins, such as vinylidene acetones, nitroole-fins, enones, and vinyl sulfones. In this chapter we will describe the inter- and intramolecular reactions in which activation of the carbonyl compound takes place via enamine formation. 

The survey in Figure 9.23 shows that N nucleophiles can react with carbonyl compounds in the following ways (1) An addition to the C=0 double bond followed by an SN1 reaction leads to the formation of AW-acetals (details Section 9.2.4). (2) An addition to the C=0 double bond is followed by an El reaction by which, amongst others, enamines are formed (details Section 9.3). (3) Imines are produced. We still need to discuss whether the reaction of O nucleophiles with carbonyl compounds also gives us two options—parallel to the two possibilities (1) and (2) mentioned above. According to Figure 9.12 alcohols and carbonyl compounds always afford 0,0-acetals—through an addition and an SN1 reaction (details Section 9.2.2). 

The observations that these reactions are inhibited by nitrobenzene (a free radical inhibitor), no hydrogenated by-products are formed and that CF BrCl gives only a-CFjCl carbonyl compounds, led the authors to propose a radical chain mechanism for these reactions (Scheme 1). The chain initiation step is the formation of XFiC radical and enamine radical cation by electron transfer from the enamine to BrCFjX. The addition of this perhaloalkyl radical to the enamine generates a RjNC R R" type radical which is known to have an unusually low oxidation potential with 1/2 in the range of — 1 V (sce). An electron transfer from this radical to another molecule of perhaloalkane then takes place to form the iminium salt and another perhaloalkyl radical which continues the chain. A similar mechanism operates in the case of Rp. ... 

In addition to direct formation from an arylhydrazine and a carbonyl compound, iV-aryl-hydrazones can be prepared from aryldiazonium ions by coupling with enolates or enamines (Japp-Klingemann reaction). This reaction has most frequently been applied to j -ketoesters. The coupling product undergoes deacylation so that the ultimate product of Fischer cycUzation is an indole-2-carboxylate ester (Scheme 58) <92JMC4823>. 

Briefly, the mechanism for formation of an enamine is very similar to that for the formation of an imine. In the first step, nucleophilic addition of the secondary amine to the carbonyl carbon of the aldehyde or ketone followed by proton transfer from nitrogen to oxygen gives a tetrahedral carbonyl addition compound. Acid-catalyzed dehydration gives the enamine. At this stage, enamine formation differs from imine formation. The nitrogen has no proton to lose. Instead, a proton is lost from the a-carbon of the ketone or aldehyde portion of fhe molecule in an elimination reaction. 

Route II leads (after H2O addition and enamine hydrolysis e/f) to the y-amino aldol intermediate 36. Retro-aldol reaction may follow (retroanalysis step g) resulting in the formation of a-amino carbonyl compounds 38 and methylene ketones 37 as possible starting materials for pyrrole synthesis. 

Notice that the mechanisms for imine, enamine, hydrate, and acetal formation are similar. The nucleophile in each reaction has a lone pair on its attacking atom. After the nucleophile has added to the carbonyl carbon, water is eliminated from a protonated tetrahedral intermediate, forming a positively charged species. In imine and hydrate formation, a neutral product is achieved by loss of a proton from a nitrogen and an oxygen, respectively. (In hydrate formation, the neutral product is the original aldehyde or ketone.) In enamine formation, a neutral product is achieved by the loss of a proton from an a-carbon. In acetal formation, a neutral compound is achieved by the addition of a second equivalent of alcohol. 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

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