Aldehydes self-reactions

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. 

The aldol condensation involves the formation of an anion on a carbon a to an aldehyde or ketone carbonyl group, followed by nucleophilic reaction of that anion at the carbonyl group of another molecule. The reaction may involve the self-reaction of an aldehyde or ketone or the formation of the anion of one compound and reaction at the carbonyl of a different compound. The latter is called a mixed aldol condensation. 

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... 

Mixed aldol reactions between ketones and aldehydes are frequently successful because one of the competing side reactions, self-reaction of the ketone, is endothermic. Most commonly, these mixed aldol reactions are carried out under conditions that lead to the a,p-unsaturated ketone pr uct. The principal side reaction is usually aldehyde dimerization. 

When a ketone and an aldehyde are condensed in a cross-aldol reaction, excess ketone must be used to avoid aldehyde self-condensation, and even so the surface is essentially saturated with aldehyde at low temperature. Exceptions are reactions of easily enolizable ketones at ambient and lower temperatures. Therefore increasing the temperature often increases selectivity as well, a situation reminiscent of decarboxylative condensation, by allowing for greater ketone adsorption. 

Moreover, a study has been made on the effect of fluorine substitution in the MBH reaction of various fluorocarbonyl partners with acrolein, methyl vinyl ketone, ethyl acrylate and acrylonitrile. Multifunctionalized fluorinated allyl alcohols were prepared from amine-sensitive aldehydes and olefins by balancing their reactivities. When the olefin is capable of reacting with itself in the presence of an amine e.g. acrolein), the electrophile has to be very reactive as well e.g. fluoral) to obtain a modest to good yield of MBH products. The reaction of a moderately reactive olefin e.g. ethyl acrylate or acrylonitrile) and a very reactive electrophile e.g. fluoral) resulted in self-reaction of the electrophile or very low yield of the allylic alcohol product. 

Percent product distribution acetone 24.5 5.1, 2-methyl-2-propanol 18.8 4.0, 2-methyl-2-hydroperoxypropane 36.7 7.5, 2-methyl-propanal 14.0 3.9, 2-methyl-propanol 4.4 1.3, tertiary butylperoxide < 1.7. The peroxy radicals involved are primary 2-methyl-1-propylperoxy, primary methylperoxy and tertiary 2-methyl-2-propylperoxy. The relatively large yield of tertiary butanol is due to the interaction between CH3OO and tertiary butylperoxy radicals. Computer simulations based on the known rate coefficients for the self-reactions of these radicals [2] gave = 3 x 10" cm molecule s for the cross combination reaction. To simulate the observed ratio of primary alcohol and aldehyde requires a rate coefficient p 3 x 10" cm molecule s for the interaction between 2-methyl-1-propylperoxy and tertiary 2-methyl-2-propyl-peroxy radicals. The oxidation mechanism is quantitatively well understood. 

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 aldol reaction is a reaction between two carbonyl-containing compounds. In a self-condensation aldol, the same carbonyl starting material is used as both the nucleophile and the electrophile. In other cases, it is possible to have a mixed aldol, which reacts one ketone/aldehyde with a different ketone/ aldehyde. Such reactions would require some means of controlling the regio-chemistry of the reaction. 

The netv reaction conditions effectively suppressed aldehyde self-aldolization. The main side product vas now the corresponding acetone cross aldol condensation product, typically formed in comparable yields vrith the desired aldol addition product. 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Reactions with Aldehydes and Ketones. The base-catalyzed self-addition of acetaldehyde leads to formation of the dimer, acetaldol [107-89-1/, which can be hydrogenated to form 1,3-butanediol [107-88-0] or dehydrated to form crotonaldehyde [4170-30-3]. Crotonaldehyde can also be made directiy by the vapor-phase condensation of acetaldehyde over a catalyst (53). 

Reactions and Uses. The common reactions that a-hydroxy acids undergo such as self- or bimolecular esterification to oligomers or cycHc esters, hydrogenation, oxidation, etc, have been discussed in connection with lactic and hydroxyacetic acid. A reaction that is of value for the synthesis of higher aldehydes is decarbonylation under boiling sulfuric acid with loss of water. Since one carbon atom is lost in the process, the series of reactions may be used for stepwise degradation of a carbon chain. 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

The formation of a-acetoxyketones by oxidation of enamines with thallic acetate has been studied in detail (27) and found to be of preparative value (80 % yields) particularly in five- and six-membered-ring ketone derivatives. Enamines of linear or seven-membered-ring ketones were oxidized also, but at very much slower rates. Enamines of aldehydes with a-hydrogen substituents underwent self-eondensations during the oxidation reactions. Lead tetraacetate was less satisfactory as an oxidizing agent. 

A few other aldehydes have been used in the reaction, either under normal or pseudo-physiological conditions. Of these, glycolalde-hyde, 5-hydroxypentanal, phenylacetaldehyde, and benzalde-hyde condense readily, but hydroxy and methoxy derivatives of these aromatic aldehydes give the product in poor yield,presumably due to their instability, as evidenced by their tendency to undergo self-condensation in acid solution. Reaction with phthaldehydic acids, such as opianic acid, proceeded readily, whereas reaction with chloral did not occur,... 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

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