Base-catalyzed aldol condensation

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. 

KNOEVENAGEL OOEBNER STOBBE Condensation Base catalyzed aldol condensation of aldehydes or ketones with an activated methylene group of a malonic ester (Knoevenagel Doebner) or a succinic ester (Stobbe)... 

Aldol condensation is catalyzed by base, but not by the cobalt catalyst. This allows the pathway from aldehyde to alcohol to be studied separately with aldehyde as starting material and under conditions that preclude aldol condensation. For example, condensation is minimal in the absence of a base or with an aldehyde whose carbon skeleton has a branch adjacent to the aldehyde group. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

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). 

Allyl aryl ethers are used for allylation under basic conditionsfh], but they can be cleaved under neutral conditions. Formation of the five-membered ring compound 284 based on the cyclization of 283 has been applied to the syntheses of methyl jasmonate (285)[15], and sarkomycin[169]. The trisannulation reagent 286 for steroid synthesis undergoes Pd-catalyzed cyclization and aldol condensation to afford CD rings 287 of steroids with a functionalized 18-methyl group 170]. The 3-vinylcyclopentanonecarboxylate 289, formed from 288, is useful for the synthesis of 18-hydroxyestrone (290)[I7I]. 

The base-catalyzed reaction of acetaldehyde with excess formaldehyde [50-00-0] is the commercial route to pentaerythritol [115-77-5]. The aldol condensation of three moles of formaldehyde with one mole of acetaldehyde is foUowed by a crossed Cannizzaro reaction between pentaerythrose, the intermediate product, and formaldehyde to give pentaerythritol (57). The process proceeds to completion without isolation of the intermediate. Pentaerythrose [3818-32-4] has also been made by condensing acetaldehyde and formaldehyde at 45°C using magnesium oxide as a catalyst (58). The vapor-phase reaction of acetaldehyde and formaldehyde at 475°C over a catalyst composed of lanthanum oxide on siHca gel gives acrolein [107-02-8] (59). 

Diketones are readily transformed to cycHc derivatives, such as cyclopentanones and furans. In this manner, the fragrance dihydrojasmone (3-meth5l-2-pentyl-2-cyclopenten-l-one) is prepared by the base-catalyzed aldol condensation of 2,5-undecanedione. 2,5-Undecanedione is itself prepared from heptanal and methyl vinyl ketone in the presence of thiazoHum salts (329). i7j -Jasmone can be similarly prepared (330,331). 

Fusion of SIX membered nngs by reactnn of cyclanones with vinyl ketones (base or acd catalyzed), a tandem Michael addition aldol condensation... 

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. 

Aldehydes and ketones with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction called the aldol reaction. For example, treatment of acetaldehyde with a base such as sodium ethoxide or sodium hydroxide in a protic solvent leads to rapid and reversible formation of 3-hydroxybutanal, known commonly as aldol (aidehyde + alcohol), hence the general name of the reaction. 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

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. 

Benzaldehydes are not subject to base catalyzed aldol condensations, and under the reaction conditions Cannizarro reactions are not important. 

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

Another advantage of this method is that no catalyst is needed for the addition reaction this means that the base-catalyzed polymerization of the electrophilic olefin (i.e., a,j8-unsaturated ketones, esters, etc.) is not normally a factor to contend with, as it is in the usual base-catalyzed reactions of the Michael typCi It also means that the carbonyl compound is not subject to aldol condensation which often is the predominant reaction in base-catalyzed reactions. An unsaturated aldehyde can be used only in a Michael addition reaction when the enamine method is employed. 

A possible mechanism for the P-alkylation of secondary alcohols with primary alcohols catalyzed by a 1/base system is illustrated in Scheme 5.28. The first step of the reaction involves oxidation of the primary and secondary alcohols to aldehydes and ketones, accompanied by the transitory generation of a hydrido iridium species. A base-mediated cross-aldol condensation then occurs to give an a,P-unsaturated ketone. Finally, successive transfer hydrogenation of the C=C and C=0 double bonds of the a,P-unsaturated ketone by the hydrido iridium species occurs to give the product. 

The Knoevenagel condensation is a cross-aldol condensation of a carbonyl compound with an active methylene compound leading to C-C bond formation (Scheme 7). This reaction has wide application in the synthesis of fine chemicals and is classically catalyzed by bases in solution (146,147). 

Aldol condensation of acetone is a well-known base-catalyzed reaction, and barium hydroxide is one of the catalysts for this reaction mentioned in textbooks. A family of barium hydroxide samples hydrated to various degress determined by the calcination temperature (473, 573, 873, and 973 K) of the starting commercial Ba(OH)2 8H2O were reported to be active as basic catalysts for acetone aldol condensation (282,286). The reaction was carried out in a batch reactor equipped with a Soxhlet extractor, where the catalyst was placed. The results show that Ba(OH)2 8H2O is less active than any of the other activated Ba(HO)2 samples, and the Ba(OH)2 calcined at 473 K was the most active and selective catalyst for formation of diacetone alcohol, achieving nearly 58% acetone conversion after 8h at 367 K in a batch reactor. When the reaction temperature was increased to 385 K, 78% acetone conversion with 92% selectivity to diacetone alcohol was obtained after 8h. The yield of diacetone alcohol was similar to that described in the literature in applications with commercial barium hydroxide, but this catalyst required longer reaction times (72-120 h) (287). No deactivation of the catalyst was observed in the process, and it could be used at least 9 times without loss of activity. 

Alkane production from sugars by aqueous phase dehydration/hydrogenation reactions has the advantage that most of the alkane fraction is spontaneously separated from the aqueous phase. Unfortunately, the major compound produced by this process is hexane, which has a low value as a gasoline additive due to its relatively high volatility. This limitation has been partially overcome by promoting a base-catalyzed aldol condensation step which links carbohydrate-derived units via formation C-C bonds to form heavier alkanes ranging from C to C15 [151]. 

Duval and Cuny reported the total syntheses of hyellazole (245) and 6-chlorohyellazole (246) starting from diketoindoles 777a and 777b (606). In this methodology, the key step is the base-catalyzed intramolecular aldol condensation of the ketoindoles to fully functionalized 3-hydroxycarbazoles. 

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. 

---