Aldol reactions self-addition

Mixed aldol condensations can be effective only if we limit the number of reaction pos sibilities It would not be useful for example to treat a solution of acetaldehyde and propanal with base A mixture of four aldol addition products forms under these condi tions Two of the products are those of self addition... 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

Self-addition of fragments occurs by the familiar, base-catalyzed, aldol mechanism. This reaction shows general, base catalysis,139-140 indicating that the rate-controlling step is the formation of the anion (80). As it is this anion that is liberated in the cleavage process of the... 

Exercise 24-11 Nitriles of the type RCH2CN undergo a self-addition reaction analogous to the aldol addition in the presence of strong bases such as lithium amide. Hydrolysis of the initial reaction product with dilute acid yields a cyanoketone, O CN... 

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... 

Several of the aldol products obtained were readily converted to their corresponding esters by Baeyer-Villiger oxidation. These results also are summarized in Table 16. Ester 66 was further transformed into key epothilone A intermediate 69 and also a key synthetic intermediate 70 for bryostatin 7. What is the mechanism of these direct catalytic asymmetric aldol reactions using LLB-II It is apparent that self-assembly of LLB and KOH occms, because of the formation of a variety of aldol products in high ee and yields. In addition, the NMR and LDI-TOF(-i-)MS spectra of LLB KOH show the occurrence of rapid exchange between Li and K. We have already found that LPB[LaK3tris(binaphthoxide)] itself is not a useful catalyst for aldol reactions, and that the complexes LPB KOH or LPB LiOH give rise to much less satisfactory results. 

Mg enolates generated from Mg bisamides can be used in aldol addition reactions with alkyl, aryl, and cyclic ketones. As shown in Scheme 3.40, these reactions are significant in that the self-coupling of ketones in aldol reactions to give tertiary yS-hydroxyketones are also possible. More specifically, these transformations are achieved principally by the use of relatively high reaction temperatures between 25 °C and 60 °C. Such conditions are a notable departure from the widely used lithium-mediated aldol additions, where increasing the reaction temperature results in retro-aldol processes and also elimination of LiOH to give enone products [30]. 

Lithium enolates do not even solve all problems of chemoselectivity most notoriously, they fail when the specific enolates of aldehydes are needed. The problem is that aldehydes self-condense so readily that the rate of the aldol reaction can be comparable with the rate of enolate formation by proton removal. Fortunately there are good alternatives. Earlier in this chapter we showed examples of what can go wrong with enamines. Now we can set the record straight by extolling the virtues of the enamines 96 of aldehydes.17 They are easily made without excessive aldol reaction as they are much less reactive than lithium enolates, they take part well in reactions such as Michael additions, a standard route to 1,5-dicarbonyl compounds, e.g. 97.18... 

Directed aldol condensation. Aldol condensation between an aldehyde and a ketone usually is not successful because self-addition of the aldehyde is the preferred reaction. Wittig and Reiff,1 however, showed that, if the aldehyde is first converted into a Schiff base (cyclohexylamine was used) and then metalated with lithium di-isopropylamide (chosen for obvious stcric reasons), aldol condensation can be achieved, usually in good yield.2 In the case of ketones, this route is superior to olefination via a phosphorylide. 

Base-catalyzed self-addition of aldehydes to form -hydroxy aldehydes is successful under mild conditions, but only with relatively low molecular weight aldehydes examples are presented in equations (7) and (8). The rule of thumb is that aldehydes of up to alraut six carbons can be dimerized in aqueous and alcoholic medium by such methods. Attempts to force the addition reaction of higher molecular weight aldehydes by using more vigorous conditions result in dehydration of the initial aldols, with for-... 

The formose reaction in detail, however, consists of a series of reactions primary self-addition of formaldehyde followed by aldol reaction of products with each odier and with formaldehyde. Cannizzaro and cross-Cannizzaro reactions occur, as well as Lobry de Bruyn-Alberda van Ekenstein rearrangements. Product decomposition (for example, to chromophores) occurs if the reaction conditions are unduly severe. The monosaccharides formed are all dl (racemic), with no optical rotatory... 

The Cannizzaro reaction of formaldehyde is far from a simple kinetic process that could be characterized by first- or second-order kinetics, and that would be a single reaction in which methanol and formate are produced. Rather, it proceeds in alkaline medium in conjunction with the formose reaction, the autocatalytic self-addition of formaldehyde to produce glycolaldehyde, which is then followed by aldol reaction to afford higher aldoses and ketoses. Mono-, di-, tri-, and tetra-valent bases, as well as nitrogenous bases, have been reported to catalyze both reactions homo-... 

Aldol Reaction (Condensation) [24] Traditionally, it is the acid- or base-catalyzed condensation of one carbonyl compound with the enolate/enol of another, which may or may not be the same, to generate a P-hydroxy carbonyl compound— an aldol. The method is composed of self-condensation, polycondensation, generation of regioisomeric enols/enolates, and dehydration of the aldol followed by Michael addition, q.v. The development of methods for the preparation and use of preformed enolates or enol derivatives that dictate specific caibon-caibon bond formation have revolutionized the coupling of carbonyl compounds (Fig. 6.6) ... 

Reactions between ketone donors and aldehyde acceptors strrMigly depend on the nature of the aldehyde. While a-disubstimted aldehydes normally react easily, unbranched ones often undergo self-addition reactions. List et al. reported one of the first examples of a direct aldol addition of ketones to a-unbranched aldehydes en route to a natural product in 2001 (44). The operationally simple reaction between 13 and 19 in the presence of catalytic amounts of (5)-12 furnished the enantiomerically enriched p-hydroxy-ketone 20 in moderate yield. The reduced yield can be rationalized by the concomitant formation of the crmdensation product 21, which is one of the limiting factors in such reactions (besides the self reaction of a-unbranched aldehydes). Intermediate 20 can then be further converted to the bark beetle pheromone (5)-ipsenol (22) in two more steps (Scheme 6). 

The experiment presented in this section is an example of a mixed-or crossed-aldol condensation. This term describes cases in which two different carbonyl compounds are the reactants. Such reactions are synthetically practical under certain circumstances, selectively producing a single major condensation product. For example, a ketone may preferentially condense with an aldehyde rather than undergoing self-addition with another molecule of itself (Scheme 18.3). This is because the carbonyl carbon atom of ketones is sterically and electronically not as susceptible to nucleophilic attack as is that of aldehydes. The aldehydic partner in such a reaction generally has no a-hydrogen atoms, so that it is unable to undergo an aldol reaction. 

The aldol condensation is considered to be one of the most important carbon-carbon bond forming reactions in organic synthesis in presence of basic reagents. The conventional aldol condensation involve reversible self-addition of aldehydes containing a a-hydrogen atom. The formed P-hydroxy aldehydes... 

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