The Aldol Condensation of Ketones and Aldehydes

Mechanism 22-6 Base-Promoted Halogenation 1054 Mechanism 22-7 Final Steps of the Haloform Reaction 1056 Mechanism 22-8 Acid-Catalyzed Alpha Halogenation 1058 22-6 Alpha Bromination of Acids The HVZ Reaction 1059 22-7 The Aldol Condensation of Ketones and Aldehydes 1060... 

Enol silyl ethers react with aldehydes with a catalytic amount of TBAF to give the aldol silyl ethers in good yields. These reactions generally proceed under very mild conditions and within shorter periods of time than conventional strong acidic or basic conditions. The products from4-f-butyl-l-methyl-2-(trimethylsilyloxy) cyclohexene and benzaldehyde show very good axial selectivity and a little anti-syn selectivity (eq 20). The aldol condensation of ketones and aldehydes can be achieved in one pot when ethyl (trimethylsilyl)acetate is used as a silylation agent with TBAF (eq 21). 

Aluminum oxide has been one of the most frequently used reagents for self-condensation of ketones and aldehydes. However applications of aluminum-mediated aldol reactions to cross-coupling have appeared only recently in the literature. Aluminum reagents, in common with other Lewis acids, form aldol product chelates so that unwanted side reactions such as dehydration or secondary condensation may be avoided. ... 

Cyclopentenones. Both aldol condensation of ketones with aldehydes and subsequent Nazarov cyclization of the products to yield polysubstituted cyclopentenones are catalyzed by zirconyl chloride. 

Aldol Reactions.—Anhydrous lithium iodide in ether is an effective reagent for the formation of a./S-unsaturated ketones via aldol condensations between ketones and aldehydes [equation (44)].In the presence of trimethylsilyl chloride and triethylamine, the aldol product is trapped as the silyl ether derivative, as a mixture of stereoisomers. 

In Summary Treatment of enolizable aldehydes with catalytic base leads to jS-hydroxy aldehydes at low temperature and to a,jS-unsaturated aldehydes upon heating. The reaction proceeds by enolate attack on the carbonyl function. Aldol addition to a ketone carbonyl group is energetically unfavorable. To drive the aldol condensation of ketones to product, special conditions have to be used, such as removal of the water or the aldol formed in the reaction. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

Diastereoselective aldol condensations.1 The aldol condensation of a chiral ethyl ketone such as 2 with aldehydes catalyzed by Bu2BOTf gives a mixture of all four possible diastereomeric adducts with little or no stereocontrol. In contrast, reactions catalyzed by either (+)- or (- )-l are highly diastereoselective. By proper choice of (+)- and (- )-l and of (+)- and (- )-2, each one of the four possible 1,2-yyn-diastereomers can be obtained in high purity. 

In order to test these assumptions Heathcock prepared different chiral ketones. Thus, the aldol condensation of the fructose-derived ketone and the acetonide of (/ )-glyceraldehyde gave poor results in the double stereodifferentiation, since an almost equal mixture of the two jyn-aldols 68a and 68b were obtained. However, the reaction with the (5)-aldehyde gave only one syn adduct (69a) (Scheme 9.22) ... 

Another general method for the preparation of 19,19,19- and 20,20,20-trifluor-oretinals involves the aldol condensation of trifluoroacetone with an ethylenic aldehyde. When performed in the presence of acetic acid and piperidine, it affords an a, S-unsaturated ketone. Applied to cyclocitral and its homologues, the method leads to polyenic trifluoromethyl ketones. From these ketones, the various tri-fluorinated retinoids are prepared by known methods (Figure 4.24). ... 

In the aldol condensation of prostereogenic ketones 5 and aldehydes 6 there are four possible product stereoisomers. Both relative (llent-1 vs. S/ent-S, syn vs. anti) and absolute (7 vs. ent-7 and 8 vs. ent-S) configuration must be determined100. 

Aldol condensation. Anhydrous lithium iodide (ca. 5 equivalents) promotes aldol condensation of ketones with enolizable or nonenolizable aldehydes. The intermediate aldol is usually not isolable, but can be intercepted by addition of ClSi(CH3)3 and N(C2H5)3. In this case Lil can be used in a catalytic amount. The salt cannot be replaced by LiBror LiCl or Nal. 

For conversion of ketones into a,/3-unsaturated aldehydes containing two additional carbon atoms, several multistep processes via ethynyl or vinyl carbinol intermediates have been reported.4-10 Although the overall yields obtained by these routes for the conversion of cyclohexanone into cyclohexylideneacetaldehyde have never exceeded 50%, they were the only useful methods for this type of conversion until the excellent process of Wittig11 appeared. This process consists of normal aldol condensations of ketones with the lithium salt of ethylidenecyclohexylamine and subsequent dehydration and hydrolysis. 

A broad spectrum of a,/J-unsaturated carbonyl compounds becomes accessible in this way because a great variety of aldehydes is suited for aldol condensation. Table 13.7 exemplifies the broad scope by way of the reactions of an aldehyde enolate (center) and of the enolate of an unsymmetrical ketone (right). The right column of Table 13.7 also shows that the regio-selectivity of the aldol condensation of the ketone is not easy to predict. Subtle substituent... 

Olefinic aldehydes and ketones result from the dehydration of the corresponding /5-hydroxy compounds. The availability of olefinic compounds by this method is subject to the limitations of the aldol condensation (method 102) and the mode of dehydration. The tendency for dehydration to a conjugated system (a,/S-olefinic compounds) is not as pronounced as is generally believed. 

With respect to the enol, this mechanism is similar to that of halogenation (12-4). A side reaction that is sometimes troublesome is further condensation, since the product of an aldol reaction is still an aldehyde or ketone. The aldol condensation of aldehydes has also been done using a mixture of pyrrolidine and benzoic acid. ... 

Many reactions of ketones and aldehydes as for instance the aldol condensation or the haloform reaction 55 are initiated by enolate anions. In these cases, a proton linked to the a carbon is removed, producing an enolate that reacts with electrophiles 1A. It has been found that in gas phase, the oxygen is the most reactive site, whereas the a carbon is mostly attacked in condensed phase. 

The synthesis of methyl ketone 281 began with the reaction between the tetra-substituted allylborane 279 and 2,3-0-isopropylidene-D-glyceraldehyde 48. The resulting homoallylic alcohol 280, obtained in 73% yield and excellent selectivity (exact ratio not defined) [231], was converted in two steps to the methyl ketone 281. Aldol condensation between the lithium enolate of 281 and aldehyde 278 (structure shown in Scheme 11-12) gave, after protection of the initial adduct, the Felkin diastereomer 282 as the only reported product in 54% yield. This adduct... 

As shown in many of the foregoing examples, aldol condensation of an aromatic aldehyde with a ketone normally provides the ( )-a,3-unsaturated ketone. This stereochemical generalization has been investigated by Hassner and Mead. ° It was found that even very hindered ketones such as 2,2-diphenylcyclohexanone give the ( )-enone under mild conditions (equation 69). The (Z)-enone is obtained quantitatively by irradiation in alcoholic solution, but this isomer is easily transformed back to the ( )-isomer. 

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