Aldol aldehyde/ketone

The aldol reaction yields either a /3-hydroxy aldehyde/ketone or an a, 3-unsatu-rated aldehyde/ketone, depending on the experimental conditions. By learning how to think backward, it s possible to predict when the aldol reaction might be useful in synthesis. Whenever the target molecule contains either a /3-hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction. 

The product is a P-hydroxy aldehyde (called an aldol) or ketone, which in some cases is dehydrated during the course of the reaction. Even if the dehydration is not spontaneous, it can usually be done easily, since the new double bond is in conjugation with the C=0 bond so that this is a method of preparing a,P-unsaturated aldehydes and ketones as well as P-hydroxy aldehydes and ketones. The entire reaction is an equilibrium (including the dehydration step), and a,P-unsaturated and P-hydroxy aldehydes and ketones can be cleaved by treatment with OH (the retrograde aldol reaction). There is evidence that an SET mechanism can intervene when the substrate is an aromatic ketone. ... 

Supplement 1941 1-161 Derivatives. Methyl alcohol, 273. Ethyl alcohol, 292. Ethyl ether, 314. Glycerol, 502. Carbonyl Compounds Aldehydes, Ketones, Ketencs and Derivatives. Formaldehyde, 558. Acetaldehyde, 635. Acetone, 635. Ketene, 724. Hydroxy-Carbonyl Compounds Aldehyde-Alcohols, Ketone-Alcohols, Monosaccharides and Derivatives. Glycolaldehyde, 817. Aldol, 824. Pentoses, 858. Hexoses, 878. 

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. 

Scheme 32 Unsaturated aldehydes, ketones and esters in the hydroformylation/Mukayama aldol reaction...

Simple aliphatic nitriles, aldehydes, ketones and esters are not readily alkylated under liquiddiquid phase-transfer conditions. Direct alkylation of aldehydes under even mildly basic phase-transfer conditions has to compete with aldol and Cannizzaro reactions and yields are low and variable [e.g. 6], a,a-Disubstituted aldehydes are C-alkylated, e.g. formylcyclohexane has been alkylated (>70%) with a range of reagents using benzyltrimethylammonium isopropoxide as the basic catalyst [7], whereas a-unsubstituted alkanals tend to undergo aldol condensation under basic liquid liquid two-phase conditions [8]. 

A straightforward method for aldolizing unsymmetrical ketones on the more hindered side involves the use of catalytic titanium(lV) chloride in toluene at room temperature. For examples using acyclic and cyclic ketones, and linear, branched, and aromatic aldehydes, the regioselectivity varied from 7 1 to >99 1, while the symanti ratios were moderate to good, and yields were in the range 62-91%. In contrast to other methods, base is not required, and the ketone can be used as is (i.e. the silyl enol ether is not required). 

In spite of the attractiveness of the aldol manifold, there are several problems that need to be addressed in order to render the process catalytic and effective. The first problem is a thermodynamic one. Most aldol reactions are reversible. Furthermore, the equilibrium is also just barely on the side of the prodncts in the case of simple aldehyde-ketone aldol reactions [79, 80]. In the case of ketone-ketone aldol reactions, the equilibrinm generally lies on the side of starting materials (Scheme 14). Overall, this means that relatively high concentrations of starting materials should be used, and very often one of the components mnst be used in excess. 

Originally, the term aldol condensation referred specifically to the reaction of an aldehyde (having an a-hydrogen) with an aldehyde/ketone to form a j8-hydroxy aldehyde (the aldol). The reverse reaction is often referred to as a retrograde aldol reaction, a retro-aldol condensation (or reaction), or an aldol cleavage. March categorizes aldol condensations into five classes. The first is condensation between two identical aldehydes... 

Aldol reaction 1 Aldehyde —CH—CHO Ketone —CH—COR 1 Aldehyde, ketone Dehydration may follow... 

Keywords Aldol, Direct, Ketone, Asymmetric catalysis, Enantioselective reaction, Diastereo-selectivity, 1,2-Diol, Aldehyde, Enamine, Lewis acid, Bronsted base, Organocatalysis, Bimetal-... 

Keywords aldehyde, ketone, Aldol condensation, chalcone... 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

A short review examines the current status and prospects for the direct asymmetric aldol-Tishchenko reaction, a process which allows for stereocontrol of three con- tiguous chiral centres in three-aldehyde or aldehyde-ketone-aldehyde reactant combinations.139... 

The presence of a carbon—carbon double bond conjugated to a carbonyl group (an a,/3-unsaturated aldehyde, ketone, and so on) in the target compound suggests that an aldol condensation be employed ... 

Diisobutylaluminum benzenetellurolate, prepared from diphenyl ditellurium and diisobutylaluminum hydride, adds in a 1,4-fashion to a,/i-unsaturated aldehydes, ketones, and carboxylic acid esters to give as intermediates /i-phenyltelluro-substituted aluminum enolates that can be hydrolyzed to the carbonyl compounds or reacted with aldehydes to produce aldol adducts2. 

The first step of the total synthesis of 31 is the (7v )-proli nc-calal yzcd aldol reaction between 4 and 32, which gave the aldol adduct 33 with a good yield (69%) and nearly perfect stereocontrol (>96% de, >99% ee, Scheme 10). The same results were observed when the reaction was carried out on a 40-mmol scale yielding 5.22 g of 33 without a decrease of selectivity. The free hydroxyl group of 33 was quantitatively protected as MOM-ether. After hydrogenolytic debenzylation the aldehyde-ketone was obtained after Dess-Martin oxidation followed by a double Wittig reaction to provide the bisolefine 34 in 41% yield over 4 steps (Scheme 10). 

Further kinetic evidence for the importance of enols comes from work on the base-catalyzed condensations of carbonyl-containing compounds. There are a number of such reactions characteristic of aldehydes, ketones, carboxylic acids, esters, amides, etc. Of these the most elementary appear to be the aldol condensations, which are prototypes of the others. These reactions can be represented by the equation... 

Stereoselective aldol condensations. Ketones react with 1 in the presence of ethyldiisopropylamine to form (Z)-boron enolates with high stereoselectivity. These derivatives react with aldehydes to afford primarily erythro- -ketols after oxidation and alkaline hydrolysis. ... 

Imines and their derivatives could be used in an analogous way to aldehydes, ketones, or their derivatives this subject has been reviewed [79]. A competition experiment between an aldimine and the corresponding aldehyde in the addition to an enol silyl ether under titanium catalysis revealed that the former is less reactive than the latter (Eq. 14) [80]. In other words, TiCU works as a selective aldehyde activator, enabling chemoselective aldol reaction in the presence of the corresponding imine. (A,0)-Acetals could be considered as the equivalent of imines, because they react with enol silyl ethers in the presence of a titanium salt to give /5-amino carbonyl compounds, as shown in Eqs (15) [81] and (16) [79,82]. 

Table 2. Aldol reactions of ketene silyl acetals with aldehydes, ketones, and acetals.

Cross aldol reaction between two different aldehydes and/or ketones without prior activation or protection should provide a straightforward methodology for the synthesis of aldols, Mahrwald recently reported that treatment of aldehydes with TiCU and NEta (or TMEDA) gives rise to syn- do reaction in good yields (Eqs 38 and 39) [141], This method was extended to the aldehyde-ketone cross aldol reaction catalyzed by TiCU [142], an advantage of which is that reaction occurs at the more encumbered a-position of unsymmetrical ketones, as illustrated in Eqs (40) and (41) [143], The use of aliphatic aldehydes instead of PhCHO usually reduced stereoselectivity. When TiCU was replaced by a catalytic amount of BuTi(0-/-Pr)4Li, the aldol reaction was followed by the Tischenko reaction [144], Methyl vinyl ketone trimerized to give a chlorinated cyclic product with TiCU [145],... 

Aldehyde Ketone Entry (R ) (R2) (eq) Aldol Time (h) Yield (%) ee %) Yield of ester ... 

Enolate anions are an important class of carbanions that appear in a variety of important reactions, including alkylation a- to a carbonyl group and the aldol (reaction 16-34) and Claisen condensation (reaction 16-85) reactions. Metal enolate anions of aldehydes, ketones, esters, and other acid derivatives exist as aggregates in ether solvents, and there is evidence that the hthium enolate of... 

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

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