Ketone enolates aldol reactions

It is thus possible to look at a molecule such as A below and recognize that it is a ft-hydroxy ketone and thus could be formed in a crossed-aldol reaction between enolate B and aldehyde C. Likewise D could potentially be produced by dehydration of the aldol product of cyclohexanone... 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

Aldol reaction. Silyl enol ethers react with aldehydes at 25° to give aldols - the presence of BiCl, (5 mole %). The classical version (Mukaiyama, 6, 590- 11 of this reaction usually requires a full equivalent of TiCl4 as the promotor. 7>,e BiCl, version permits use of ketones as well as aldehydes in reactions carried ut at 25°, but a longer time is required and yields are only moderate (20-65%). Both versions show only slight diastereoselectivity. 

In fact, even very weak bases are enough for most l, 3-dlcarbonyI compounds and piperidine and acetic acid combine to form a mild buffered system that facilitates both conjugate addition and aldol reactions via enol Intermediates. The trifluoromethyl ketone is extremely electrophilic so the aldol reaction proceeds very smoothly. 

Kocienski and coworkers [98] have reported the synthesis of 8-membered cyclic ketones by intramolecular aldol reaction of enol silanes and acetals mediated by Lewis acid. 

Aldehydes and ketones react by nucleophilic addition. In an aldol reaction, an enolate is the nucleophile that adds to the carbonyl group. 

The different methods available for doing aldol reactions with enolates of aldehydes, ketones, and esters... 

In the Evans synthesis of the polypropionate region (Scheme 9-45), the boron-mediated anti aldol reaction of -ketoimide ent-25 with a-chiral aldehyde 145 afforded 146 with 97% ds in what is expected to be a matched addition. Adduct 146 was then converted into aldehyde 147 in readiness for union with the C -Cs ketone. This coupling was achieved using the titanium-mediated syn aldol reaction of enolate 148 leading to the formation of 149 with 97% ds. 

More impressive and more important is the performance of these lithium enolates in aldol reactions. Ester enolates are awkward things to use in reactions with enolisable aldehydes and ketones because of the very efficient self-condensation of the aldehydes and ketones. The traditional solutions involve such devices as Knoevenagel-style reactions with malonates.11 Lithium enolates of esters, e.g. 76, react cleanly with enolisable aldehydes and ketones to give high yields of aldols,12 e.g. 79 in a single step also involving a six-membered cyclic transition state 77. 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

The direct aldol reaction of carboxylic acid derivatives and aldehydes (or ketones) is very difficult. Recently, Kobayashi and co-workers (146) extended the ketones to amides as suitable candidates successfully for the direct aldol reaction. The screening of metal sources revealed that Ba(0-tBu)2 was the better catalyst than Sr(0-iPr)2, Ca(0-iPr)2, or Mg(0-iPr)2, whereas rare earth metals (eg, La(0-iPrls) are catalytically inactive in the presence of p-methoxyphenol. In this aldol reaction, barium enolate formed in situ from barium alkoxide and acylamide and... 

In the aldol reaction, an enolate ion attacks the carbonyl group of an aldehyde or ketone (Section 18-5) to furnish a j8-hydroxycarbonyl product. A process that is quite analogous is the Mannich reaction. Here, however, it is an enol that functions as the nucleophile and an iminium ion, derived by condensation of a second carbonyl component with an amine, as the substrate. The outcome is a j8-aminocarbonyl product. 

The Reformatskii reaction resembles an aldol reaction because a enolate anion attacks a carbonyl group to give an a-hydroxy carbonyl compound. In an aldol reaction, the enolate is derived from an aldehyde or ketone. In the Reformatskii reaction, the enolate is derived from an ester. 

Corey also developed a class of C2-symmetric diazaborolidines (cf 146), which have been successfully applied in asymmetric aldol reactions of enolates of thioesters, esters, and ketones [80-82]. In this context, the anti-aldol adduct 150 (dr 98 2, 94% ee) was isolated from the reaction of benzaldehyde with trans-ester enolate 148, while the ds-thioester enolate 152 produced syn aldol product 154 (dr 98 2, 94% ee, Scheme 4.15) [81]. Close inspection of the adducts obtained from the addition of the trans- and cis-enol borolidines reveals that they differ not only in relative configuration (syn versus anti) as expected, but also in the facial selectivity with respect to the aldehyde [82]. 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

A useful catalyst for asymmetric aldol additions is prepared in situ from mono-0> 2,6-diisopropoxybenzoyl)tartaric acid and BH3 -THF complex in propionitrile solution at 0 C. Aldol reactions of ketone enol silyl ethers with aldehydes were promoted by 20 mol % of this catalyst solution. The relative stereochemistry of the major adducts was assigned as Fischer- /ir o, and predominant /i -face attack of enol ethers at the aldehyde carbonyl carbon atom was found with the (/ ,/ ) nantiomer of the tartaric acid catalyst (K. Furuta, 1991). 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

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