Aldol reaction, self

When a normal carbonyl compound is treated with catalytic acid or base, we have a small proportion of reactive enol or enolate in the presence of large amounts of unenolized electrophile. Aldol reaction (self-condensation) occurs. With 1,3-dicarbonyl compounds we have a small proportion of not particularly reactive unenolized compound in the presence of large amounts of stable (and hence unreactive) enol. No aldol occurs. 

Aldol reactions. Self-condensation of aldehydes as well as Robinson annulation are effected. The latter process is conducted in the presence of molecular sieves 4A in aprotic solvents such as toluene. 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

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.

Aldol condensations were originally carried out in the liquid phase and catalysed homogeneously by acids or bases this way of operation is still predominant. Solid-catalysed aldol reactions can also be performed in the liquid phase (in trickle or submerged beds of catalyst), but in many cases vapour phase systems are preferred the factors determining the choice are the boiling points and the stability of the reactants at elevated temperatures. At higher temperatures, the formation of a, j3-unsaturated aldehydes or ketones [reactions (B) and (C)] is preferred to aldol (ketol) formation [reaction (A)]. A side reaction, which may become important in some cases, is the self-condensation of the more reactive carbonyl compound if a mixed condensation of two different aldehydes or ketones is occurring. The Cannizzaro reaction of some aldehydes or polymerisation to polyols or other resin-like products can also accompany the main reaction. 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Mixed aldol reactions may be broadly classified as the reaction between two different aldehydes or ketones, or the reaction of an aldehyde with a ketone. Apart from the concomitant self-condensation, not less than two possible crossed products can be envisaged. Such reactions are therefore only prepara-tively useful either if appropriate structural conditions are present, or if certain experimental conditions are used to effect a directed aldol condensation. 

E. Westerlund, Formation of 3-octuloses by a self-aldol reaction of D-erythrose, Carbohydr. Res., 91 (1981) 21-30. 

Extensions of the proline-catalyzed aldol reaction Recently interesting extensions of the enantioselective proline-catalyzed aldol reaction have been reported. An enan-tioselective proline-catalyzed self-aldolization of acetaldehyde was observed by Barbas and co-workers (Scheme 6.21) [77]. Starting from acetaldehyde, the valuable building block 5 -h ydroxy-( 2E)-hexcnal, (S)-43, was obtained as a product with up to 90% ee, although the yield did not exceed 13%, irrespective of the reaction conditions. This reaction requires a small amount catalyst only (ca. 2.5 mol%). 

Disconnection 37 again uses the natural polarity of the carbonyl group but at the next bond 37 since we hope to use some enolate derivative 38 in an alkylation reaction. But—and it is a big but—do not think for a moment that you can make 37 just by mixing the ketone 39 with an alkyl halide and some base. The problem is that the ketone is itself electrophilic and the self-condensation by the aldol reaction (chapter 19) is generally preferred to alkylation. 

Most of the examples in this chapter have been of molecules without selectivity. They have indeed all been self condensations. We hope this has established the basic disconnections and the chemistry but we must now turn to examples where selectivity is needed. So the ketone 46 was made to study aldol reactions with aromatic aldehydes.13 They found that, in acid or base, the enone 52 was the main product with the best yield from HCI in EtOH. The product 52 was isolated as its HCI salt. In this case it is easy to see that only the ketone can enolise, that the aldehyde is more electrophilic than the ketone and that the geometrical isomer shown is the more stable. Such considerations are the substance of the next chapter. 

They are useful for ketones too. Disconnection of the enone 99 reveals an aldol reaction between cyclopentanone 74 and the enolisable ketone 100. Control is needed solely to prevent self-condensation of the aldehyde. 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

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... 

A basic amine catalyst may promote the self-aldol reaction of the aldehyde, having an enolizable carbonyl. This reaction can be particularly important in the case of slowly reacting hindered aldehydes. In order to avoid this secondary reaction, a number of trialkylphosphines were tested and, in non-asymmetric reactions, tributylphosphine was generally found to be the most effective [32, 33],... 

So far we have considered only self-condensations1—dimerization reactions of a single carbonyl compound. These form only a tiny fraction of known aldol reactions. Those that occur between two different carbonyl compounds, one acting as a nucleophile in its enol or enolate form, and the other as an electrophile, are called cross-condensations. They are more interesting than self-condensations, but working out what happens needs more thought. 

In other cases the balance may shift towards self-condensation. You might think that a crossed aldol reaction between acetaldehyde and benzophenone (diphenylketone Pli2C=0) should work well. 

The silyl enol ether is not isolated but reacted immediately with the aldehyde to give an excellent yield of the aldol. Dehydration in acid solution with toluene sulfonic acid (TsOH) gives the enone. You can see by the high yield in the aldol reaction that there is no significant self-condensation of either partner in the aldol reaction. 

These silyl enol ethers are probably the best way of carrying out crossed aldol reactions with an aldehyde as the enol partner. An example is the reaction of the enol of the not very enolizable iso-butyraldehyde with the very enolizable 3-phenylpropanal. Mixing the two aldehydes and adding base would of course lead to an orgy of self-condensation and cross-couplings. 

The enolization of ketones, unless they are symmetrical, poses a special problem. Not only do we need to prevent them self-condensing (though this is less of a problem than with aldehydes), but we also need to control which side of the carbonyl group the ketone enolizes. In this section we shall introduce aldol reactions with unsymmetrical ketones where one of two possible enols or enolates must be made. 

Diketones also self-condense rather easily in an intramolecular aldol reaction to give a cyclopentenone with an all-carbon five-membered ring, til is too is a useful reaction but we need to know how to control it. The usual rule is ... 

The lower yield may be explained by the fact that linear aldehydes also undergo self-aldol condensation, which is in direct competition with the crossed-aldol reaction. Aromatic aldehydes as the carbonyl component led to reduced diastereoselectivity. For example, the (.S )-prolinc-catalyzed aldol reaction of 4 with ort/tochlorobenzaldehyde proceeded with a good yield of 73%, but with an anti/syn ratio of only 4 1 and enantiomeric excesses of 86% ee (anti) and 70% ee (syn). 

This mixed aldol will succeed because one of the components, benzaldehyde, is a good acceptor of nucleophiles, yet has no cc-hydrogen atoms. Although it is possible for acetone to undergo self-condensation, the mixed aldol reaction is much more favorable. 

Seebach has proposed the participation of an oxazoUdinone intermediate along the reaction pathway of the proline-catalyzed aldol reaction, driven by the NMR observation of this species in the reaction mixture. Sharma and Sunoj employed DPT and MP2 computations to assess whether the oxazoUdinone is actuaUy on the reaction pathway. They examined the proUne-catalyzed self-aldol reaction of propanal, for which MacMillan has experimentaUy shown an ee of... 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

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