A Crossed Aldol Addition

If two different carbonyl compounds are used in an aldol addition— known as a crossed aldol addition—four products can be formed because reaction with hydroxide ion can form two different enolate ions (A and B ) and each enolate ion can react with either of the two carbonyl compounds (A or B). A reaction that forms four products clearly is not a synthetically useful reaction. 

Primarily one product can be obtained from a crossed aldol addition if one of the aldehydes does not have any a-hydrogens and, therefore, carmot form an enolate ion. That cuts the possible products from four to two. Then, if the aldehyde with a-hydrogens is added slowly to a solution of the aldehyde without a-hydrogens and hydroxide ion, the chance that the aldehyde with a-hydrogens, after forming an enolate ion, will then react with another molecule of its parent carbonyl compound will be minimized, so the possible products are cut to essentially one. 

If one of the carbonyl compounds does not have any a-hydrogens, then the compound with a-hydrogens is added slowly to a solution of the compound without a-hydrogens and a base. 

This crossed aldol condensation is sufficiently important to be given its own name— the Claisen-Schmidt condensation. 

If both aldehydes have a-hydrogens, primarily one aldol addition product can be formed if LDA is used to remove the a-hydrogen that creates the enolate ion. Because LDA is a strong base, all of the carbonyl compound will be converted into an enolate ion, so none of that carbonyl compound will be left for the enolate ion to react with in an aldol addition. Therefore, an aldol addition will not be able to occur until the second carbonyl compound is added to the reaction mixture. If the second carbonyl compound is added slowly, the chance that it will form an enolate ion and then react with another molecule of its parent carbonyl compound will be minimized. 

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The preceding reaction is called a mixed aldol addition or a crossed aldol addition. The four products have similar physical properties, making them difficult to separate. Consequently, a mixed aldol addition that forms four products is not a synthetically useful reaction. 

Recall that LDA causes irreversible enolate formation. If acetaldehyde is added dropwise to a solution of LDA, the result is a solution of enolate ions. Propionaldehyde can then be added dropwise to the mixture, resulting in a crossed aldol addition that produces one major product. This type of process is called a directed aldol addition, and its success is hmited by the rate at which enolate ions can equilibrate. In other words, it is possible for an enolate ion to function as a base (rather than a nucleophile) and deprotonate a molecule of propionaldehyde. If this process occurs too rapidly, then a mixture of products will result. 

A crossed Claisen condensation is a condensation reaction between two different esters. Like a crossed aldol addition, a crossed Claisen condensation is a useful reaction only if it is carried out under conditions that foster the formation of primarily one product. Otherwise, the reaction will form a mixture of products that are difficult to separate. 

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

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... 

Significant for cross-aldol reactions, when an aldehyde was mixed with (S)-proline in a reaction solvent, the dimer (the self-aldol product) was the predominant initial product. Formation of the trimer typically requires extended reaction time (as described above). Thus, it is possible to perform controlled cross-aldol reactions, wherein the donor aldehyde and the acceptor aldehyde are different. In order to obtain a cross-aldol product in good yield, it was often required that the donor aldehyde be slowly added into the mixture of the acceptor aldehyde and (S)-proline in a solvent to prevent the formation of the self-aldol product of the donor aldehyde. The outcome of these reactions depends on the aldehydes used for the reactions. Slow addition conditions can sometimes be avoided through the use of excess equivalents of donor or acceptor aldehyde - that is, the use of 5-10 equiv. of acceptor aldehyde or donor aldehyde. In general, aldehydes that easily form self-aldol products cannot be used as the acceptor aldehydes in... 

Only one of the aldol condensations of Table 13.7 (top, center) concerns the reaction of a carbonyl compound with itself. In all other reactions of Table 13.7, the ,/i-unsaturated carbonyl compounds are formed by two different carbonyl compounds. Such aldol condensations are referred to as crossed aldol condensations (cf. the discussion of crossed aldol additions in Section 13.3.1). 

Benzaldehyde, cinnamic aldehyde, and their derivatives do not contain any a-H atoms therefore, they can participate in crossed aldol additions only as electrophiles. 

Directed aldol reaction (Section 24.3) A crossed aldol reaction in which the enolate of one carbonyl compound is formed, followed by addition of the second carbonyl compound. 

The aldol addition reaction is one of the most versatile carbon-carbon bond forming processes available to synthetic chemists. The addition reaction involves readily accessed starting materials and can provide )9-hydroxy carbonyl adducts possessing up to two new stereocenters. The previous decade witnessed many substantive advances in the crossed aldol addition reaction as a result of the development of a variety of well-defined enolization protocols and the evolution of highly sophisticated understanding of the reaction mechanism. Moreover, the design of highly effective chiral auxiliary-based systems has allowed for impressive levels of stereocontrol in a number of asymmetric aldol processes. 

The aldol condensation involves the reaction of two molecules of an aldehyde or ketone that has alpha hydrogens. Abstraction of an alpha hydrogen by base produces a carbanion which attacks the carbonyl carbon of the other molecule by base-initiated nucleophilic addition an alcohol group is formed. Often the alcohol dehydrates to form the final product, an unsaturated aldehyde or ketone. In a crossed aldol condensation, a carbonyl compound with alpha hydrogens reacts with one without alpha hydrogens. 

In a manner analogous to the earlier boron wc (Section 1.7.2.1), an effort has been made to generate alkenyloxyalanes from a,p-unsaturated carbonyl compounds by 1,4-addition of aluminum reagents. The addition of MeaAlSPh or Me2AlSeMe to an a,p-unsaturated carbonyl compound produces a 3-sub-stituted alkenyloxyalane derivative, which upon reaction with an aldehyde gives a crossed aldol product. 

The use of lanthanide metal enolates in the aldol reaction has, to date, only been developed to a synthetically useful level in the case of cerium (Scheme S and Table 7). Stereoselectivities are no better than those of lithium enolates, but the cerium enolates of ketones woik well in crossed aldol additions to ketones (Table 7, entries 1-7) and sterically hindered aldehydes (Table 7, entries 9 and 10). Such crossed aldol reactions do not often work well with lithium enolates as enolate equilibration, retroaldolization and steric retardation of addition occur. Imamoto et al. have shown that cerium enolates (44), formed from anhydrous CeCb (1.2 equiv.) and the preformed lithium enolates of ketones in THF at -78 C, undergo such aldol reactions to give the corresponding p-hydroxy ketones (46), usually in high yield. The cerium suppresses the retroaldol reaction by efficient chelation of the aldolate (45). A similar effect is known for zinc halide mediated aldol reactions (Volume 2, (Chapter 1.8). The stereoselectivity of the... 

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... 

With 41 in hand, a two-step nitro reduction and protection, followed by partial reduction of the lactam and resulting cyclization furnished aminal 42. Further treatment with cyanogen azide generated Wcyanoamidine 43. Hydrolysis and amide protection followed by alkylation with allyl iodide yielded olefin 44 as a single diastereomer. Conversion of 44 to aldehyde 45 was the followed reaction of the mesylate with azide, a cross-aldol reaction with acetone, lactam reprotection with Boc, and trimethylphosphine-mediated reductive rearrangement to provide spiro-y-lactam 46. Methyllithium addition to lactam 46 and similar chemistry as reported by Qin et al. gave communesin F (17) (Scheme 6). 

A crossed aldol reaction is most effective when one of the carbonyl compounds is more reactive toward nucleophilic addition and cannot form an enolate anion. (15.2)... 

Scheme 5.131 Domino hydroformylation-cross aldol addition with a chiral rhodium catalyst and a chiral aldol condensation catalyst.

Crossed aldol, or mixed aldol, reactions are aldol reactions that occur between different partners and are only efficient if one partner lacks a protons or if a directed aldol addition is performed. 

In addition to crossed aldol additions and crossed Claisen condensations, a ketone can undergo a crossed condensation with an ester. If both the ketone and the ester have a-hydrogens, then LDA is used to form the needed enolate ion and the other carbonyl compound is added slowly to the enolate ion to minimize the chance of its forming an enolate ion and reacting with another molecule of its parent ester. 

The cross-aldol addition of a ketone to an aldehyde (Claisen-Schmidt reaction) is profitably carried out by using the silyl enol ether of the ketone in an organic solvent in the presence of TiCh (Mukaiyama reaction) [2], but this protocol is not suitable for acid-sensitive substrates. High pressure may be employed in place of the catalyst, but longer reaction times are required [4]. 

Most enzymes used by Nature for carbon-carbon bond formation and cleavage ( lyases ) catalyze a crossed aldol reaction in the form of a reversible, stereocontrolled addition of a nucleophilic ketone donor to an electrophilic aldehyde acceptor. Synthetically the most useful and most extensively studied enzymes use aldol donors comprising 2-carbon or 3-carbon fragments and can be grouped into fom categories depending on the structure of their nucleophilic component (Figme 5.2) (i) pyruvate-... 

Tertiary amines undergo reversible conjugate addition to a, 3-unsaturated ketones (see Chapter 18). This process is the basis for the Bayhs-HUhnan reaction, which is catalyzed by tertiary amines, that resembles a crossed aldol reaction. An example is shown below. 

The best performance vi as obtained when glycolaldehyde vi as added slowly by means of a syringe pump, then the rate of cross-aldol addition vi as greatly enhanced. 

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