Aldol reactions cross-addition

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). 

If only one of the two aldehydes has an a-hydrogen, only two aldols can be formed and numerous examples have been reported, where the crossed aldol reaction is the major pathway. For two different ketones, similar considerations do apply in addition to the unfavorable equilibrium mentioned above, which is why such reactions are seldom attempted. 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

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... 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

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. 

In addition to enol silyl ethers, other derivatives of aldehydes and ketones, i.e. enol ethers (Eq. 8) [48] and enol esters (Eq. 9) [49, 50], serve as a partners for the cross aldol reaction, although the lower reactivity of these compounds compared with enol silyl ethers often makes the reaetion more complicated. For example, the products isolated in Eq. (8) were ether derivatives or a,y8-unsaturated carbonyl compounds rather than the expected aldol itself. 

Zr(0-f-Bu)4 is a mild reagent that can be used in cross-aldol reactions and intramolecular aldol reactions without the basic treatment of the starting ketones, whereas the use of CpaZrCl enolate gave unsatisfactory results. For example treatment of bromo-ketone (9) with Zr(0-f-Bu)4 followed by the addition of aldehyde (10) gave a-bromo-/8-hydroxyketone (11) in 56 % yield (Eq. 4) [4],... 

Other examples The addition reaction of lithium enolates of ketones to 1,2-epoxides to afford the a-alkyl-y-hydroxyketones. (a) P. Crotti, V. D. Bussolo, L. Favero, M. Pineschi, M. Pasero, J. Org. Chem. 1996, 61, 9548-9552. The cross-aldol reactions between ketones and aldehydes, (b) S. Fuku-zawa, T. Tsuchimoto, T. Kanai, Bull. Chem. Soc. Jpn. 1994, 67, 2227-2232. 

The first catalytic, diastereoselective and enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantioselectivity. ... 

The catalyhc efficiency of L-proline in ionic liquid was enhanced by the addition of DMF as cosolvent, which may be largely due to tlie increased mass transfer in the presence of DMF [79c]. Thus, the use of only 5 mol% L-proline was sufficient to accomplish the cross-aldol reactions of aliphatic aldehydes, affording a-alkyl-P-hydroxyaldehydes with extremely high enanhoselectivihes (>99% ee) in moderate to high diastereoselectivities (diastereomeric raho 3 1 >19 1). However, under the same reaction conditions, much lower ee-values and yields were observed in a one-pot synthesis of pyranose derivahves by sequential cross-aldol reachons. The L-proline immobilized in the ionic liquid layer could be recovered and reused without any deterioration in catalytic efficiency, with the diastereoselectivity,... 

The discovery of the Lewis acid-mediated addition of enol silanes to aldehydes and acetals by Mukaiyama and coworkers pioneered a novel approach to the construction of molecules via the crossed aldol reaction (Eq. 1) [6a6bj. Importantly, this development proved to be a key lead for the subsequent evolution of this C-C bond forming reaction into a catalytic Si atom-transfer process. Typical enol silanes derived from esters, thioesters, and ketones are unreactive towards aldehydes at ambient temperatures. However, stoichiometric quantities of Lewis acids such as TiCl4, SnCl4, AlClj, BClj, BF3-OEt2, and ZnCl2 were found to pro-... 

Additionally, organocatalytic cross-aldol reactions catalyzed by cyclic secondary amines in aqueous media provide a direct route to a variety of aldols, including carbohydrate derivatives, and may warrant consideration as a prebiotic route to sugars [12a],... 

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... 

Corey, Enders and Bock were among the first to describe the utility of lithium dimethylhydrazone anions for crossed aldol reactions. In the reaction shown in equation (14), an azaallyllithium reagent derived from an aldehyde dimethylhydrazone was first silylated with trimethylsilyl chloride to yield a silyl aldehyde dimethylhydrazone. Subsequent lithiation using lithium diethylamide at -20 C for 1 h generated the silylated azaallyllithium reagent (29). Subsequent addition of one equivalent of an aldehyde or ketone at -78 C and warming to -20 C then yielded the product a,p-unsaturated aldehyde dimethylhydrazone in yields of 85-95%. Hydrolysis produced the unsaturated aldehyde in 75% overall yield. 

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