Enolates crossed aldol condensation

The coupling of a secondary alcohol 1 with a primary alcohol 2 is achieved by the temporary removal of from each substrate which generates the ketone 3 and aldehyde 4 intermediates. A crossed aldol condensation occurs under the reaction conditions by the enolate derived from ketone 3 undergoing nucleophilic addition... 

Crossed aldol condensation reactions may present a problem because multiple products can be formed. For example, a mixture of carbonyl A and carbonyl B can give two different enolates, each of which can then attack either an A or a B molecule. Therefore, four products are possible (Ag, A + B, B + A, and B2). 

If die enolate nucleophile is derived from an aldehyde or ketone different than die carbonyl electrophile, a crossed-aldol condensation results. Normally best success is achieved if the carbonyl electrophile employed for the crossed-aldol condensation is more reactive than the carbonyl electrophile from which the enolate is derived. For example, ketone etiolates react with aldehydes effectively, but aldehyde enolates do not give the crossed aldol with most ketones but self-condense instead. 

Under acidic conditions enamines such as compound A in Figure 12.18 and aldehydes undergo condensation to form the conjugated iminium ions D. These will be deprotonated by the concomitantly formed hydroxide ions, In this way dienamines of type F are formed, which will then be hydrolyzed upon acidic workup to give a carbonyl group. The generation of the a,/i-unsaturated ketones E is thus completed. You will learn about type E compounds in Section 13.4.1 in connection with the so-called crossed aldol condensation products. It should be noted that it is not possible to form the same unsaturated ketone by reacting cyclopentanone or its equilibrium fraction of enol with an aliphatic aldehyde. Instead, a cyclodehydration of... 

When the enolate of one aldehyde (or ketone) adds to the carbonyl group of a different aldehyde or ketone, the result is called a crossed aldol condensation. The compounds used Crossed Aldol in the reaction must be selected carefully, or a mixture of several products will be formed. Condensations Consider the aldol condensation between ethanal (acetaldehyde) and propanal shown below. Either of these reagents can form an enolate ion. Attack by the enolate of ethanal on propanal gives a product different from the one formed by attack of the enolate of propanal on ethanal. Also, self-condensations of ethanal and propanal continue to take place. Depending on the reaction conditions, various proportions of the four possible products result. 

A crossed aldol condensation can be effective if it is planned so that only one of the reactants can form an enolate ion and so that the other compound is more likely to react with the enolate. If only one of the reactants has an a hydrogen, only one enolate will be present in the solution. If the other reactant is present in excess or contains a particularly electrophilic carbonyl group, it is more likely to be attacked by the enolate ion. 

The stereochemical course of several Co2(CO)6-mediated reactions has been studied. For example, although alkynyl aldehydes undergo crossed aldol condensation with trimethylsilyl enol ethers with little stereoselectivity, their hexacarbonyldicobalt derivatives react with moderate to excellent syn diastereoselectivity.96 101 The mechanism behind this selectivity has not been fully elucidated and is complicated by the lluxional nature of the intermediate cations. This stereoselective reaction has been successfully applied to the synthesis of /3-lactam antibiotics.100... 

We find that we need a crossed aldol condensation between two ketones so tve chemoselectivity. We also need to make one enol(ate) from an unsymmetrical ketone so v. r regioselectivity too. The obvious solutions are a lithium enolate, a silyl enol ether, or a come with an extra ester group. 

When one of the carbonyl compounds cannot form an enolate (as with HCHO, PhCHO, or Ph2CO), crossed aldol condensations are feasible. " ... 

Since nitrogen is less electronegative than oxygen, imines are less reactive toward carbanions than ketones or aldehydes are. Therefore imine enolate anions can be prepared without self- condensation, yet they will rapidly add to carbonyl compounds [9]. This amounts to a directed cross aldol condensation and can even be used to add aldehyde enolate equivalents to ketones. 

The synthesis of the ant alarm pheromone mannicone 117 is a good example. Enone disconnection reveals that we need a crossed aldol condensation between the symmetrical ketone 118, acting as the enol component, and the enolisable aldehyde 119. 

Cyclodextrins with two imidazole groups on the primary hydroxyl side can enhance the enolate formation [86] of a simple bound ketone by bifunctional acid-base catalysis and accelerating the intramolecular aldol condensation of bound ketoaldehyde and dialdehyde. The aldolase mimics which catalyzed crossed aldol condensations were obtained by the assembly of (i-CD and various amino moieties as Schiff base [87]. 

The alkoxyalkylation reaction of carbonyl compounds can be considered as an orientated cross-aldol condensation between two masked carbonyl compounds, an acetal and a silyl enol ether. The key step involves the formation of an electrophilic species by reaction of the acetal with catalytic amounts of a Lewis acid and the right catalyst can lead to excellent diastereo- and enantio-selectivities. Clays are satisfactory catalysts in these reactions, with the acid-treated clay K10 performing better than the more powerfully acidic clay KSF,... 

Full details of the previously reported (Vol. 6, p. 73) synthesis of the seco-illudane sequiterpenoid hypacrone (346) have been published. An interesting feature of the synthetic route is the use of a directed crossed aldol condensation between the diketone (344) and the trimethylsilyl enol-ether (343) to produce the trans-isomer (345) of hypacrone (346). The absolute configuration of fomannosin (347) has finally been established by X-ray analysis of the camphanate ester derivative (348). Full details of the biosynthesis of fomannosin (347) from [l,2- C2]acetate (c/. Vol. 7, pp. 82, 196) have been published. The labelling pattern and couplings in fomannosin (347) are consistent with a biosyn-... 

Cross aldol condensation. This aldol condensation has also been carried out with a variety of keto esters and sUyl enol ethers. The reaction is carried out in methylene chloride at 20° wi+h equimolecular amounts of reactants and titanium(lV) chloride. Only the keto group reacts under these conditions and dehydration of the products is not observed. 

There are certainly cases when we want a crossed-aldol condensation between two reactive partners that have an enolizable position, as in 3-pentanone with cyclopentanone. If 3-pentanone and benzaldehyde, which has no enolizable protons, can lead to three products, what will happen in this new case If an aldol condensation occurs under thermodynamic conditions. 3-pentanone reacts with sodium ethoxide to give enolate 120. This enolate can condense with either unenolized 3-pentanone (to produce 126) or with unenolized cyclopentanone (to produce 128). Both of these ketones are symmetrical, and there is no opportunity for additional enolates, which would further complicate the reaction (see below). The pAa of 3-pentanone and cyclopentanone are not... 

Good crossed aldol condensations require one component to enolize and act as a nucleophile and the other not to enolize and to act as the electrophile. Here follows a list of carbonyl substituents that prevent enolization and therefore force a carbonyl compound to take the role of the electrophilic partner. They are arranged roughly in order of reactivity with the most reactive towards nucleophilic attack by an enolate at the top. You do, of course, need two substituents to block enolization so typical compounds also appear in the list. Note that the last two entries—esters and amides—do not normally do aldol reactions with enolates, but they do react as acylating agents for enolates, as you will see later in this chapter. 

When the enolate of one aldehyde (or ketone) adds to the carbonyl group of another, the result is called a crossed aldol condensation. The compounds used in the reaction must be selected carefully, or a mixture of several products will be formed. 

We shall therefore consider crossed aldol condensations by two general approaches that allow control over the distribution of products. The first approach hinges on structural factors of the carbonyl reactants and the role that favorable or unfavorable aldol addition equilibria play in determining the product distribution. In this approach relatively weak bases such as hydroxide or an alkoxide are used in a protic solvent such as water or an alcohol. The second approach, called a directed aldol reaction, involves use of a strong base such as LDA in an aptotic solvent. With a strong base, one reactant can be converted essentially completely to its enolate, which can then be allowed to react with the other carbonyl reactant. 

You will perform the crossed-aldol condensation of acetophenone (21) with p-anisaldehyde (4-methoxybenzaldehyde, 23) to give frans-p-anisalacetophenone (25) according to the sequence outlined in Scheme 18.4. For steric and electronic reasons, the enolate ion 22 reacts preferentially with 23 rather than 21, leading to the aldol 24. This product then dehydrates in the presence of base, in the manner outlined in Equation 18.11, to yield the condensation product 25. Part of the thermodynamic driving force for this dehydration is associated with forming a new carbon-carbon ir-bond that is conjugated with the aromatic ring as well as with the... 

The choice of an aldehyde such as 2-methylpropanal (26) having only one a-hydrogen atom is important to the success of this crossed-aldol condensation because its dimerization is of no consequence. For example, aldehyde 26 can readily react with another molecule of itself to give 35 (Eq. 18.13), but this process is reversible under the reaction conditions. Moreover, unlike the aldol product 34,35 is incapable of dehydrating to give an a,p-unsaturated product and water, which would drive the equilibrium leading to the dimerization product. It is left to you to consider the possibility of self-condensation of 3-buten-2-one (27) and of the reaction of enol 30 with the carbon atom of the protonated carbonyl function in 31 (see Exercises 12 and 13 at the end of this section). 

This crossed aldol reaction between acetone and an aldehyde may be carried out successfully by treating acetone with one equivalent of LDA to convert it completely to its enolate anion. The preformed enolate is then treated with the aldehyde followed by workup in water to give the crossed aldol condensation product. 

FIGURE 19.96 Amide bases are often used in crossed aldol condensations of esters and ketones. They lead to formation of the kinetic enolate through removal of the most accessible hydrogen. 

As in the crossed aldol condensation, there are some simple steps we can take to improve matters. If one of the starting esters has no a hydrogen, there can be no eno-late formation from it, and it can act only as an electrophile, never as a nucleophile. It is helpful to add the ester wth an a hydrogen to a mixture of the partner without an a hydrogen and the base. As the enolate is formed it is more likely to react with the ester that has no a hydrogen since it is present in excess. Using this technique, a successful crossed Claisen can be achieved. Benzoates, formates, and carbonates are examples of esters without a hydrogens and are often used (Fig. 19.109). 

Kinetics (Section 8.8) The study of the rates of reactions. Knoevenagel condensation (Section 19.6) Any of a number of condensation reactions related to the crossed aldol condensation. A stabilized anion, often an enolate, is first formed and then adds to the carbonyl group of another molecule. Dehydration usually leads to the formation of the final product. 

If an a,p-nnsaturated ketone is treated with an enolate, a mixture of products is obtained. Not only do we observe both possibilities (the enolate attacking the earbonyl group, or the enolate attacking the f) position), bnt it gets even more comphcated. The product of the 1,4 addition is a ketone, which can be attacked again by an enolate. You can get crossed aldol condensations, and all sorts of unwanted products. So, we can t use an enolate to attack an a,(i-unsaturated ketone. The enolate is simply too reactive, and we observe a mixture of undesired products. 

Crossed Aldol Condensations Using Strong Bases Lithium Enolates and Directed Aldol Reactions... 

A remote functionalization sequence which employs a tandem retro-[l, 4] Brook rearrangement to transfer a silyl moiety of an acetophenone silyl enol ether to the ortho position of the aromatic ring, has been developed see Scheme 11. The enolate (35) derived from this process has been used in cross-aldol condensations to afford ketones (36). 

Lithium enolates of a-chloroacyltrimethylsilanes react with two equivalents of an aldehyde to form the a,jS Unsaturated aldehyde and a carboxylic acid in good yield (Scheme 30). A Cannizzaro-type mechanism is proposed. The method is equivalent to the specific crossed aldol condensation of two aldehydes. 

Bivalent tin enolates may also be used in cross-aldol condensations between two ketones. In reactions of tin enolates with aliphatic ketones, little stereoselectivity is observed, but with aromatic ketones (such as acetophenone), the major diastereoisomer formed is the threo-xsomtt [equation (51)]. The reaction... 

Ketone 55 and aldehyde 54 were then joined via a crossed aldol condensation. The resulting alcohol was oxidized to give 56. The enolate derived from /3-dicarbonyl 56 was O-acylated at C9. The C7 carbonyl group was reduced to the alcohol oxidation state with concomitant reductive cleavage of the enol acetate. Treatment of the resulting j8-hydroxy ketone with mesyl chloride gave 57. 

What happens if we try to carry out an aldol condensation between the enolate of one aldehyde and the carbonyl carbon of another In such a situation, called crossed aldol condensation, mixtures ensue, because enolates of both aldehydes are present and may react with the carbonyl groups of either starting compound. For example, a 1 1 mixture of acetaldehyde and propanal gives the four possible aldol addition products in comparable amounts. 

In Summary Crossed aldol condensations furnish product mixtures unless one of the reaction partners cannot enolize. 

Aldehyde enolates present another problem. They tend to give selfcondensation before an electrophile can be added. This may be solved again by use of imine enolates or A,A-dimethylhydrazones, which are themselves of low electrophihcity and allow good crossed aldol condensations and alkylations. For example, the terf-butyl imine of propanal was converted to the enolate with LDA and used in a crossed aldol condensation (Eq. 7.16) [30]. 

Crossed aldol condensations [37] between dissimilar ketones may be carried out under Lewis acid conditions using the silyl enol ether of that ketone intended as the nucleophile. This affords the aldols without dehydration or polycondensation (Eq. 7.21) [38]. 

Diketones are produced by a crossed aldol condensation between an aldehyde or ketone enolate and an ester. 

The Mukaiyama aldol reaction is a highly selective cross aldol condensation using a silyl enol ether as nucleophile and a Lewis acid-coordinated carbonyl compound as electrophile. 

An exceptionally mild procedure for the cross-condensation of aldimines and enolsilanes has been described (eq. [67]) (80). This titanium tetrachloride-mediated reaction is predicated on the previous analogies provided by Mukaiyama for related aldol condensations (73a). Depending on aldimine structure and reaction time, either -lactams or their penultimate amino esters may be isolated from the reaction. The authors postulate that these reactions are proceeding via titanium enolates derived from ligand exchange by... 

An aldol reaction/condensation occurs when the enolate ion from an aldehyde or ketone attacks a molecule of the parent compound. If, however, two different carbonyl compounds are present, a crossed aldol reaction/ condensation occurs. 

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. 

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