Carbonyl compounds enamine catalysis

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. 

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). ... 

A range of nitrogen, phosphorus, chalcogen (O, S, Se) and halogen electrophiles react with enamines, resulting in a net a-functionalization of the carbonyl compound. In the past five years, all of these reaction variants have been subjected to asymmetric enamine catalysis, with excellent results. 

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. 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

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... 

If you want to do a conjugate addition of a carbonyl compound without having a second anion-stabilizing group, you need some stable and relatively unreactive enol equivalent. In Chapters 27 and 28 you saw how enamines are useful in alkylation reactions. These neutral species are also perfect for conjugate addition as they are soft nucleophiles but are more reactive than ends and can be prepared quantitatively in advance. The reactivity of enamines is such that heating the reactants together, sometimes neat, is all that is required. Protic or Lewis acid catalysis can also be used to catalyse the reaction at lower temperature. 

In 2007, Connon and McCooey developed highly efficient, asymmetric syn-selective addition reactions of enolizable carbonyl compounds to nitroolefins by adopting the enamine catalysis approach [48]. The 9-epi-amino cinchona alkaloid derivative (160,9 -epi-DHQDA) as an aminocatalyst promoted the addition ofa variety... 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Acetone, the component that must enolise, is present in large excess but the achievement is considerable. The reaction involves formation of the proline enamine of acetone 91 which then attacks the aldehyde through a chair-like transition state 92 held together by the acidic proton of proline s carboxylic acid. This gives the imine salt 93 hydrolysed to the product with regeneration of proline. The intermediates are like those in the Robinson annelation enamines and imines. Organic catalysis with amines relies on equilibria between these intermediates and carbonyl compounds. 

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. 

The asymmetric a-allqrlation of carbonyl compounds constitutes one of the fundamental organic transformations for the construction of carbon-carbon bonds, and has long been the Achilles heel for asymmetric aminocatalysis. Towards a solution to this long-standing problem, Jacobsen and coworkers have shown that the enantioselective a-allqrlation of a-arylpropionaldehydes with diarylbromonethane can be carried out under the catalysis of primary-amine thiourea 39 (Scheme 19.60). Catalyst 39 reacted with the aldehyde to form an enamine, followed by a S -l-type substitution induced by the bromide anion. 

The use of enamine catalysis in the enantioselective a-functionalization of carbonyl compounds has been reviewed, including aldol, Mannich, and alkylation processes," and a short review has examined enantioselective a-alkylation of aldehydes Benzodithiolylium tetrafluoroborate (133) is a water-stable salt and can be added enantioselectively to aldehydes at the a-position in the presence of simple chiral organocatalysts, giving the corresponding alcohol. The sulfurs can be readily cleaved with H2/Raney Ni, rendering the process a formal tf-methylation of aldehydes." a ,/3-Unsaturated aldehydes undergo enantioselective a- and y-alkylation via dien-amine activation, using a diarylprolinol TMS ether as catalyst." ... 

Nature s aldolases use combinations of acids and bases in their active sites to accomplish direct asymmetric aldolization of unmodified carbonyl compounds. Aldolases are distinguished by their enolization mode - Class I aldolases use the Lewis base catalysis of a primary amino group and Class II aldolases use the Lewis acid catalysis of a Zinc(II) cofactor. To accomplish enolization under essentially neutral, aqueous conditions, these enzymes decrease the pKa of the carbonyl donor (typically a ketone) by converting it into a cationic species, either an iminium ion (5) or an oxonium ion (8). A relatively weak Bronsted base co-catalyst then generates the nucleophilic species, an enamine- (6) or a zinc enolate (9), via deprotonation (Scheme 4.2). 

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. 

Different groups reported in 2007 on the use of C9 amino cinchona alkaloids as catalysts for the stereoselective functionaUzation of branched carbonyl compounds. Connon and coworkers demonstrated that the C9 amino derivative of epidihydro-quinine (40) and epidihydroquinidine (41) were effective catalysts for the conjugate addition of aldehydes and (cyclic) ketones to nitroalkenes via enamine catalysis [99] (Scheme 6.46). The catalysts with the same configuration at C9 as in the natural cinchona alkaloid gave poor results, in line with the results obtained for... 

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