Acid-Catalyzed Aldol Condensation

Problem 21.12 In acid-catalyzed aldol condensations acid is believed to perform two functions to catalyze conversion of carbonyl compound into the enol form, and to provide protonated carbonyl compound with which the enol can react. The reaction that then takes place can, depending upon one s point of view, be regarded either as acid-catalyzed nucleophilic addition to a carbonyl group, or as electrophilic addition to an alkene. On this basis, write all steps in the mechanism of acid-catalyzed aldol condensation of acetaldehyde. In the actual condensation step, identify the nucleophile and the electrophile. 

Although the aldol condensation is catalyzed by acids, it has not seemed to be of any significance as a side reaction in Lobry de Bruyn-Alberda van Ekenstein transformations which have been carried out in acidic media. 

The synthesis of enones, usually a,P-unsaturated, and hydroxyktones using heterogeneous catalysis has barely been addressed (homogeneous catalysis is another story, see below). Two-step processes predominate in the patent literature, with the aldol condensation base-catalyzed and the ketol dehydration acid-catalyzed either reaction can be conducted in the liquid or gas phase. These processes are not especially selective, but there have been many years of process development behind them. 

The usual base or acid catalyzed aldol addition or ester condensation reactions can only be applied as a useful synthetic reaction, if both carbonyl components are identical. Otherwise complicated mixtures of products are formed. If two different aldehydes or esters are to be combined, it is essential that one of the components is transformed quantitatively into an enol whereas the other component remains as a carbonyl compound in the reaction mixture. 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

The 3.8-nonadienoate 91, obtained by dimerization-carbonylation, has been converted into several natural products. The synthesis of brevicomin is described in Chapter 3, Section 2.3. Another royal jelly acid [2-decenedioic acid (149)] was prepared by cobalt carbonyl-catalyzed carbonylation of the terminal double bond, followed by isomerization of the double bond to the conjugated position to afford 149[122], Hexadecane-2,15-dione (150) can be prepared by Pd-catalyzed oxidation of the terminal double bond, hydrogenation of the internal double bond, and coupling by Kolbe electrolysis. Aldol condensation mediated by an organoaluminum reagent gave the unsaturated cyclic ketone 151 in 65% yield. Finally, the reduction of 151 afforded muscone (152)[123]. n-Octanol is produced commercially as described beforc[32]. 

DIBK can be produced by the hydrogenation of phorone which, in turn, is produced by the acid-catalyzed aldol condensation of acetone. It is also a by-product in the manufacture of methyl isobutyl ketone. Diisobutyl ketone ( 1.37/kg, October 1994) is produced in the United States by Union Carbide (Institute, West Virginia) and Eastman (Kingsport, Teimessee) (47), and is mainly used as a coating solvent. Catalytic hydrogenation of diisobutyl ketone produces the alcohol 2,6-dimethyl-4-heptanol [108-82-7]. 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

Base-catalyzed aldol reactions have been carried out intramole-cularly.241 The aqueous acid-catalyzed intramolecular aldol condensation of 3-oxocyclohexaneacetaldehyde proceeded diastereoselectively (Eq. 8.95).242... 

This possible mechanism should be evaluated in relation to the catalysts. If the catalytic action is to be ascribed to the acid character of the catalysts, the condensation under consideration may differ from the ordinary aldol condensation, which is catalyzed preferentially by basic agents. Nevertheless, many condensations of the aldol type are effected with the aid of acidic reagents. Moreover, the condensation of sugars with dicarbonyl compounds has been carried out in aqueous alcoholic media which are non-acidic hence, there also exists the possibility of a mechanism catalyzed simultaneously by acid and by base, somewhat like that suggested by Lowry46 in another connection. A transition state with an amphiprotic structure has been postulated. Its formation can be catalyzed by either acids or bases. 

The iridium-catalyzed addition of water could be applied to the reaction of a,03-diynes. Thus, 1,7-octadiyne 125 was converted to l-(2-methylcyclopent-l-enyl)ethanone 127 (Equation 10.32). The formation of 127 was explained by assuming intramolecular aldol condensation of the resulting 2,7-octadione by Lewis acid. 

Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether. 

Figure 6. Synthesis of 9-0-acetyl-N-acetylneuraminic acid. The aldol acceptor was prepared from N-acetylmannosamine and isopropenyl acetate in DMF catalyzed by protease N obtained from Amano. The aldol condensation was carried out by using N-acetylneuraminic acid aldolase as catalyst.

Entries 4 and 5 in Scheme 2.1 depict acid-catalyzed aldol reactions. In entry 4, condensation is accompanied by dehydration. In entry 5, a /i-chloroketone is formed by addition of hydrogen chloride to the enone. 

There are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen-Schmidt condensation. Scheme 2.2 presents some representative examples. 

Ketal regeneration proceeds step-wise through an enol ether intermediate. This intermediate is capable of several side reactions including a copper catalyzed aldol condensation, heavies formation and addition reactions with hydrochloric acid. Hydrochloric acid addition to l-methoxycyclohexene is of no consequence since this side reaction proved to be thermally reversible under oxycarbonylation reaction conditions. 

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