Aldol-type reaction, Self

In Section 9.4.A, it was noted that there were problems with aldol-type reactions, especially with the directed aldol condensation. In particular, aldehydes with an a-hydrogen have great difficulty adding to ketones due to their propensity for self-condensation. The ability to use kinetic control conditions in enolate reactions of ketones and aldehydes often solves this problem. There are also several alternative approaches that involve the use of carbanions derived from imines and hydrazones and these can be very useful. l... 

Tables 1 and 2 show some examples of self- or cross-aldol condensation reactions followed by dehydration to obtain a,/3-unsaturated carbonyl compounds. Also in Table 1, a review of methyl isobutyl ketone (a saturated ketone) synthesis in the presence of hydrogen is included (10). In Table 2, some examples of fine chemicals obtained by aldol-type reactions are shown.

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

These aldehydes react on acid condensation with phenols to give novolac-type products. Base-catalyzed condensation is not practical with acetaldehyde since it undergoes rapid aldol condensation and self-resinification reactions. Acid condensations involving acetaldehyde or its trimer paraldehyde and phenol give soluble and permanently fusible resins, comparable to the novolacs. Aldehyde with no a hydrogens react in a manner similar to formaldehyde ... 

D-Erythrose undergoes self-aldolization in alkali solution, to form d- / co-L- /3 C6 TO-3-octulopyranose by combination of the 1,2-enediol and aldehyde forms. In weak alkali at 105°, syrupy D-erythrose yields d- /ycero-tetrulose, jS-D-a/tro-L-g/ycero-l-octulofuranose, and a-Ti-gluco-i -g/ycero-3-octulopyranose. At 300° in alkali, the major products from syrupy D-erythrose were 1-5% of butanedione (biacetyl) with smaller proportions of pyrocatechol, 33, 2,5-dimethyl-2,5-cyclohexadiene-l,4-dione (2,5-dimethylbenzoquinone), and 2,5-dimethyl-1,4-benzenediol (2,5-dimethylhydroquinone). It was assumed that D-erythrose is reduced to erythritol by a Cannizzaro type of reaction, followed by dehydration of erythritol to form biacetyl. However, very low proportions (<1%) of biacetyl are formed from erythritol compared with D-erythrose itself. Apparently, some other mechanism predominates in the formation of biacetyl. 

The effect of the basicity of aldol condensation catalysts on their activity was thoroughly investigated by Malinowski et al. [372—379]. The observed linear dependence of the rate coefficients of several condensation reactions on the amount of sodium hydroxide contained in silica gel (Figs. 12 and 13) supported the view that the basic properties of this type of catalyst were actually the cause of its catalytic activity, though the alkali-free catalyst was not completely inactive. The amphoteric nature of the catalysis by silica gel, which can act also as an acid catalyst, was demonstrated [380]. By a stepwise addition of sodium acetate to a HN03-pretreated silica gel catalyst the original activity for acetaldehyde self-condensation was decreased to a minimum (when an equivalent amount of the base was added) by further addition of sodium acetate, the activity increased again because of the transition to a base... 

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... 

This is about the most difficult type of aldol reaction two shghtly different aldehydes, both enolizable, both capable of self-condensation. The only solution is to couple the silyl enol ether of one aldehyde with the other aldehyde using a Lewis acid as catalyst. This gives the aldol itself that can be dehydrated to the enal. 

The aldol condensation is a very attractive route to a,p-unsaturated carbonyl compounds. The application of this reaction is nevertheless rather limited, since numerous side reactions usually occur amongst these are self-condensation of the ketone, Michael-type addition to the newly formed product, or Cannizzaro reactions. As a consequence, poor yields are obtained in most cases [90]. In the enol ether condensation, described earlier, these side reactions are less troublesome. A disadvantage of the enol ether condensation compared to the aldol condensation is that strongly acidic conditions have to be used to cleave the intermediate in the enol ether synthesis. 

The crossed aldol examples shown in Table 19.1 involve aldehydes as both reactants. A ketone can be used as one reactant, however, because ketones do not self-condense appreciably due to steric hindrance in the aldol adchtion stage. The following are examples of crossed aldol condensations where one reactant is a ketone. Reactions such as these are sometimes called Claisen—Schmidt condensations. Schmidt discovered and Claisen developed this type of aldol reaction in the late 1800s. 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

The acid-catalyzed aldol condensation of acetone is probably the most studied reaction of this type. As shown in Scheme 2, self-condensation of acetone yields a number of different products depending on the operating conditions and catalyst used. In particular, on acidic catalysts, the products are mainly aliphatic and aromatic hydrocarbons. A summary of the product distribution as a function of the reaction temperature on acidic zeolites can be found in Ref (65). 

Mixed aldol reactions between different aldehydes or ketones are usually plagued by formation of a mixture of products, because each component can function as a CH-acidic and carbonyl-active compound. Whereas the directed aldol reaction [14-16] is a rather general solution to this problem, the traditional aldol addition of non-identical carbonyl compounds is only successful when applied within the framework of a limited substitution pattern. Thus, a fruitful combination in mixed aldol reactions is that of an aldehyde with an enolizable ketone. Obviously, the aldehyde, having higher carbonyl reactivity, reacts as the electrophilic component, whereas the ketone, with comparatively lower carbonyl reactivity, serves as the CH-acidic counterpart. Because the self-aldolization of ketones is endothermic, this type of side reaction does not occur to a significant extent, so the product of the mixed aldol condensation is obtained in fair yield, as illustrated by the formation of ketone 6 from citral 5 and acetone, a key step in the synthesis of j5-ionone (Eq. (7)) [17]. 

The most efficient variant of this combination is based on reaction of an enolizable ketone with a non-enolizable aldehyde, so that self-condensation of the latter cannot occur. Several examples of this type of combination in aldol reactions are given in Scheme 1.2. Usually in situ elimination occurs, so a,j5-unsaturated ketones result, in particular when aromatic aldehydes are condensed with ketones ( Claisen-Schmidt reaction ) [18-21]. 

It is self-evident that the transition state hypotheses discussed above are exclusively relevant to kinetically controlled aldol additions. Although this type of reaction control is the rule when preformed enolates are used, one should be aware that the reversibility of aldol additions cannot be excluded a priori and in any instance. In aldol reactions of preformed enolates, reversibility becomes noticeable in equilibration of syn aldolates with anti aldolates rather than in an overall low yield as found in the traditional aldol reaction. Considering the chair conformations of the syn and the anti aldolates, the former seem to be thermodynamically less stable, because of the axial position of the a-substituent R. This situation is avoided in the anti adduct (Eq. 

A Mannich-type condensation mechanism involving an iminium ion electrophile similar to the aminocatalytic Knoevenagel reaction has recently been proposed for the amine-catalyzed self-aldolization of propionaldehyde (Eq. (6)) [55]. Although this mechanism is not unreasonable it should be... 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

The main problem that we face in aldol condensations is control—obviously we do not want to be limited to self-condensations in synthesis. We will discuss three main strategies for control in aldol condensations, which will also be applicable in other types of condensation reactions. These are the use of intramolecular processes forming five- or six-membered rings the use of nonenolizable, but highly electrophilic species and activation of the nucleophile by addition of another anion-stabilizing group. 

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