6-Hydroxy aldehydes, dehydration preparation

The product is a P-hydroxy aldehyde (called an aldol) or ketone, which in some cases is dehydrated during the course of the reaction. Even if the dehydration is not spontaneous, it can usually be done easily, since the new double bond is in conjugation with the C=0 bond so that this is a method of preparing a,P-unsaturated aldehydes and ketones as well as P-hydroxy aldehydes and ketones. The entire reaction is an equilibrium (including the dehydration step), and a,P-unsaturated and P-hydroxy aldehydes and ketones can be cleaved by treatment with OH (the retrograde aldol reaction). There is evidence that an SET mechanism can intervene when the substrate is an aromatic ketone. ... 

While a number of secondary )6-hydroxy silylcyclopropanes were prepared by alkylating aldehydes, their dehydration by this method has not been reported. However, a regio- and stereospecific synthesis of alkenyl(silyl)cyclopropanes from secondary 6-hydroxy silylcyclopropanes has been accomplished by dehydroxyselenation (see Section 5.2.2.7.3.). 

Entries 1 and 2 in Scheme 2.1 illustrate the preparation of aldol condensation products by the base-catalyzed reaction. In entry 1 the product is a /3-hydroxy aldehyde, while in entry 2 dehydration has provided an a,/3-unsaturated aldehyde. 

A rather special procedure for the preparation of 21-hydroxy-20-ketopreg-nanes starts with the 17a-ethoxyethynyl-17 -hydroxy steroids described earlier. Free radical addition of ethanethiol to the triple bond, followed by acid-catalyzed hydrolysis and dehydration gives the 20-thioenol ether 21-aldehyde. This can be reduced with lithium aluminum hydride to the C-21 alcohol and then hydrolyzed to the C-20 ketone in the presence of mercuric chloride. The overall yield, without isolation of intermediates, is in the order of 50% ... 

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. 

Higher-molecular-weight normal 2-alkenoic acids have been prepared in poor yields by the Doebner condensation of aldehydes with malonic acid,5-7 and by the Reformatsky reaction of aldehydes with ethyl bromoacetate followed by dehydration.8 The a-iodo acid, prepared from the bromo acid, has been dehydrohalogenated with potassium hydroxide in ethanol,9 but large quantities of the a-hydroxy acid are formed as a by-product which is difficult to separate in some instances. The present procedure is an adaptation of a published method.6... 

Adam and his co-workers have shown that sterically congested E-olefins are conveniently prepared by the lactone route shown in Scheme 7. Stereocontrol is achieved because a-lithiocarboxylates condense with aldehydes and ketones to give -hydroxy acids of predominantly r/ireo-configuration once formed, dehydrative cyclization is straightforward because the bulky substituents force the carboxy and hydroxy groups into juxtaposition. 

P-Lactones.—The enolate of phenoxyacetic acid (3,16) affords, on reaction with aldehydes, the expected /S-hydroxy-acids which can be dehydrated with ben-zenesulphonic acid to give 3-substituted-2-phenoxypropiolactones, useful precursors of phenyl enol ethers. /3-Lactones can also be prepared by the thermolysis of tri-n-butylstannyl derivatives of /8-hydroxy-esters. Hydroxy-palladation of olefins has been shown to occur in a trans manner, as reaction of [c -l,2- H2]ethylene followed by carbonylation (known to proceed with retention of configuration) gives only the tran5-substituted /3-lactone (47). ... 

The reaction of pentafluorophenylmagnesium chloride with aldehydes and ketones has been used to prepare pentafluorostyrenes via dehydration with PjOs of the intermediate alcohols. 2-Hydroxy-2-pentafluorophenyl-... 

In the presence of a strong base such as LDA, the a-carbon of acetic acid esters can react with the carbonyl group of aldehydes or ketones to give j8-hydroxy esters, which may or may not be dehydrated to a,j8-unsaturated esters. This type of reaction has been exploited for the preparation of racemic [2- C]mevalonolactone (64) (Figure 6.25) and the benzofuran[l- C]acetamide PD 126,212 (67)". In the first case a-deprotonated trimethyl-silyl [2- C]acetate was treated with l-trimethylsilyloxy-3-butanone. Acidic work-up resulted in hydrolytic cleavage of the TMS groups and formation of the lactone system... 

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