Carboxylic esters, base condensation, with aldehydes

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Carboxylic esters can be treated with ketones to give p-diketones in a reaction that is essentially the same as 10-118. The reaction is so similar that it is sometimes also called the Claisen condensation, though this usage is unfortunate. A fairly strong base, such as sodium amide or sodium hydride, is required. Yields can be increased by the catalytic addition of crown ethers. Esters of formic acid (R H) give P-keto aldehydes. Ethyl carbonate gives P-keto esters. 

Quinoxaline-2-carboxaldehyde has been converted into the 2-carboxylic acid by oxidation with potassium permanganate in acetone and reduced to the 2-hydroxymethyl compound by treatment with formalin and potassium hydroxide. It also undergoes other typical reactions of aromatic aldehydes such as benzoin formation on reaction with potassium cyanide - and condensation reactions with malonic acid and its diethyl ester and Schiff base formation. Acid-catalyzed reaction of quinoxaline-2-carboxaldehyde with ethylene glycol gives the cyclic acetal the diethylacetal has been prepared by reaction of 2-dibromomethylquinoxaline with sodium ethoxide. " An indirect preparation of the oxime 11 is achieved by treatment of 2-nitromethyl-quinoxaline (10) with diazomethane followed by thermolysis of the resulting nitronic ester. 

Some examples of the addition of one carbonyl compound to another are the aldol condensation the formation of acetoacetic ester the condensation of benzaldehyde with one of the components of a mixture of an acid anhydride and a carboxylate salt the formation of mesityl oxide, phoroiie, and mesitylene from acetone and the condensations of aromatic aldehydes and ketones. Acids and bases are generally catalysts for these reactions. They have sufficient in common to warrant their being classed together as the aldol type of... 

When the reactivity of reactant (R-CH2-X) is relatively high, the condensation reactions take place more easily than the degradation reactions. As a result, the selectivity to the condensation products becomes high. This is the case of the reaction with aldehydes or ketones. The reaction with carboxylic acids and esters is more difficult and the reaction with nitriles is the most difficult especially in view of the selectivity based on HCHO. 

The Knoevenagel reaction in its simplest form is the condensation of malonic esters (or their analogues) with aldehydes or ketones in the presence of an amine base catalyst plus a small amount of a carboxylic add (or amino add) cocatalyst. The condensation products are often a,p-unsaturated carbonyl compounds. For example. 

In an aldol reaction, an enolizable carbonyl compound reacts with another carbonyl compound that is either an aldehyde or a ketone. The enolizable carbonyl compound, which must have at least one acidic proton in its a-position, acts as a nucleophile, whereas the carbonyl active component has electrophilic reactivity. In its classical meaning the aldol reaction is restricted to aldehydes and ketones and can occur between identical or nonidentical carbonyl compounds. The term aldol reaction , in a more advanced sense, is applied to any enolizable carbonyl compounds, for example carboxylic esters, amides, and carboxylates, that add to aldehydes or ketones. The primary products are always j5-hydroxycarbonyl compounds, which can undergo an elimination of water to form a,j5-unsaturated carbonyl compounds. The reaction that ends with the j5-hydroxycarbonyl compound is usually termed aldol addition whereas the reaction that includes the elimination process is denoted aldol condensation . The traditional aldol reaction [1] proceeds under thermodynamic control, as a reversible reaction, mediated either by acids or bases. 

The methyl ester-forming attack Qq could be due to the Canizzaro-type condensation of two aldehydes, to the reaction of surface carboxylates with formyl or formaldehyde, or to the reaction of surface methoxide with an aldehyde with a hydride elimination. To be consistent with the experimental observations, we shall give an example for the last mechanism because it requires the fewest number of steps, utilizes methoxide which may be favored in hydrogen rich synthesis gas and does not require a strong base catalyst. 

A different approach to a-methylenebutyrolactones is a further development of the chemistry of 2-silyloxycyclopropane carboxylates (393), which, when treated with the trifluoromethanesulphonate analogue of Eschenmoser s salt and a Lewis acid (TMSOTf), are converted into 8-amino-esters (394) and thence lactones (395) following borohydride reduction and elimination.33 Overall yields are reasonable for this multi-step approach. A carbanion based approach to monosubstituted lactones. (390) begins by metallation and regio-selective condensation of ketene dithioacetal (396) with an aldehyde. 

Ring B pyrrole aldehyde (78) and ring C lactam (79) form under base induced condensation and subsequent introduction of sulfur the bicyclic BC thiolactam (80). This bicyclic lactam was coupled by a modification of Eschenmoser s sulfide contraction method 58) with the monocyclic chiral D building block (81) to yield after ester cleavage and complexation with nickel (II) the tricyclic intermediate (82). After hydrogenolytic cleavage of the benzylester in (82) the crude carboxylic acid formed with the ring A pyrrole aldehyde (83) the linear tetrapyrrole... 

Alcohols are hydrocarbon derivatives containing one or more OH groups. Ethers are formed by a condensation reaction of two molecules of alcohol. Several functional groups contain the carbonyl (C=0) group, including aldehydes, ketones, carboxylic acids, esters, and amides. Aldehydes and ketones can be produced by the oxidation of certain alcohols. Further oxidation of the aldehydes produces carboxylic acids. Carboxylic acids can form esters by a condensation reaction with alcohols, or they can form amides by a condensation reaction with amines. Esters imdergo hydrolysis (saponification) in the presence of strong bases. 

The second item in Table 9.5 is the Claisen condensation (not to be confused VFith the Claisen rearrangement discussed in Chapter 8, cf. Scheme 8.99). Here, an aldehyde, lacking a-protons, is allowed to react with an ester of a carboxylic acid (vide infra) in the presence of an alkoxide base. The ester must bear protons on the carbon a- to the carbonyl and the (alkoxide) base is chosen to be the conjugate base of the alcohol with which the carboxylic acid was esterified to make that ester. Thus, as... 

---