Ketones enamine activation

At present, one of the most successful catalysts for enamine activation has been proline (2). Proline is a cheap, widely and commercially available amino acid that can be found in both enantiomeric forms and, as such, represents a remarkable synthetic alternative to many established asymmetric catalysts. Given such attractive features, it has become the catalyst of choice for many enamine-catalyzed processes. However, various more recent studies have demonstrated that proline is not a universal catalyst for transformations that involve the a-functionalization of ketone or aldehyde carbonyls. Indeed, these studies have demonstrated that the iminium catalysts developed by MacMillan (imidazolidinones) and Jprgensen (pyrrolidines) are also highly effective for enamine activation with respect to... 

The sulfenylation of metalloimines is equally applicable to ketones, although using more reactive sulfur electrophiles it is possible to bring about reaction on the unmetallated enamine. ° Sulfenylation of ketone enol silyl ethers also proceeds well with the more reactive sulfur species. Sulfenamides and their derivatives e.g. 11) are particularly suited to the direct sulfenylation of ketones and active methylene compounds such as -diketones, -keto esters and malonates, which undergo facile reaction at room temperature (equation 5). This procedure, however, does not appear to have been exploited for the dehydrogenation of active methylene compounds icf. Section 2.2.4.1). By preparing the dianion (13)... 

Solvents are commonly dimethylformamide, a chloroalkane or chloroalkene (methylene chloride, chloroform, 1,2-dichloroethane, etc.) or phosphoryl chloride. Temperatures used are generally in the range CM00 C.la Substrates include activated aromatic or heteroaromatic compounds, alkenes (including enamines and enol derivatives), methyl or methylene ketones and "active methyl or methylene groups in general, and hydrazones, azines and aliphatic diazo compounds. 

Lithium aluminium hydride is also capable of reducing N-silyloxy enamines . Active methylene compounds such as open-chain and cyclic ketones can be converted into the corresponding Mannich base through the intermediacy of enaminones, which are reduced by LiAlH4 (Scheme 108). 

Figure 2.1 Primary versus secondary amine catalysts in the enamine activation of ketones.

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. 

The diflferent reactivity of aldehydes and ketones toward condensation with amines is also a differentiating element when using enals or enones as Michael donors under iminium activation. As in the enamine activation case, working with a,p-unsaturated aldehydes usually leads to faster reactions or better conversions but the same reaction with enones in many cases turns out to be a very slow or even non-existent reaction. Stereochemical control is also more problematic when a,p-unsaturated ketones are employed because the presence... 

It has to be pointed out that simple enolizable aldehydes and ketones, which are not acidic enough compounds to be directly used as pro-nucleophiles in this context, can nevertheless be employed as Michael donors in the reaction with enals or enones, which have been previously activated as the corresponding iminium ion, but their use requires prior activation via enamine activation. In these cases, it is usually proposed that the amine catalyst is involved in a dual activation profile interacting with both the Michael donor and the acceptor, although the enamine activation of the pro-nucleophile is mandatory for the reaction to occur, the activation of the acceptor being of less relevance in most cases. For these reasons, this chemistry has been covered in Chapter 2. 

The group of Moutevelis-Minakakis reported in 2014 the preparation and application of a series of tripeptides containing proline, phenylalanine and tert-butyl esters of different amino acids (see 36, Scheme 13.22c) for the asymmetric aldol reaction of aromatic aldehydes and various substituted ketones in both aqueous and organic medium. The authors assume in the proposed transition-state model, besides the well-known enamine activation, a stabilisation of the aldehyde via hydrogen-bond interactions of the two amide protons of the tripeptide with the carbonyl group of the aldehyde. The desired adducts were isolated in good to excellent yields and with very good diastereoselectivities and enantioselectivities. ... 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

This type of catalyst was also employed by Christmann et al. to promote the asymmetric intramolecular Diels Alder reaction of tethered a,p-unsaturated dialdehydes in the presence of benzoic acid as a co-catalyst through vinylogous enamine activation. The corresponding cycloadducts were obtained in good yields and excellent enantioselectivities of up to 98% ee, as shown in Scheme 6.6. When one of the aldehyde functions was replaced by an a,p-unsaturated ketone as the acceptor, no formal [4 -I- 2] cycloaddition was observed instead, a direct enantioselective vinylogous Michael addition occurred. 

On using enamine activation, nucleophiles were limited to aldehydes and ketones but the emergence of H-bonding activation [31] has expanded considerably this scope. With this mode of activation other carbon-centered nucleophiles and also heteroatom-centered nucleophiles could be considered. During the period 2003-2012, growing interest was focused on the ability to perform catalytic enantioselechve reactions with small organic molecules able to produce such weak interachons. 

The first amine-catalyzed Diels-Alder reaction of a,(i-unsaturated carbonyl compounds as dienes involving in situ enamine activation with chiral amine 29 through raising the diene HOMO energy was accomplished by Barbas and coworkers in 2002 with moderate enantioselectivity (up to 38% ee) [17a]. In 2007, Cordova and coworkers described chiral amine 29 catalyzed enantioselective Diels-Alder reactions between a,P-unsaturated cyclic ketones and nitroolefins with up to 86% ee [17b]. Two years later, Xu and coworkers successfully disclosed a highly efficient enantioselective Diels-Alder reaction of cyclohexenones 31 with aromatic nitroolefins 32 using amine 30 as catalyst in seawater or brine to give products 32 with excellent enantioselectivities (Scheme 38.10) [18a]. Notably, sea water and brine... 

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

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