Esters unsaturated Reformatsky reaction

Reformatski reaction Aldehydes and ketones react with a-bromo- fatty acid esters in the presence of zinc powder to give -hydroxy-esters which may be dehydrated to give a-, 0-unsaturated esters. a-Chloroesters will react if copper powder is used in conjunction with the zinc. 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

Both aldehydes and ketones react with the anion of ethyl trimethylsilyl-acetate to produce a/3-unsaturated esters in an alternative (13) to the Reformatsky reaction ... 

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. 

We felt the Reformatsky reaction was a worthwhile target because it is the most generally applicable method for converting aldehydes and ketones to ff-hydroxyesters(25). The improvements in yield and reaction time exceeded our expectations. Essentially quantitative conversion to the 0-hydroxyester was effected in a matter of a few minutes(26). The absence of other products, such as a, 0-unsaturated esters, resulting from dehydration, and dimers of the bromo ester and the carbonyl are probably the result of running... 

A furanose-fused c/.,(3-unsaturated 8-lactone was also prepared from ester 11 as a key chiral intermediate for the synthesis of the enantiomer of (+ )altholactone, a natural product with cytotoxic and antitumor activities.18 A Reformatsky reaction with ethylbromoacetate or a Wittig... 

Since the advent of the one step procedure for the preparation of various substituted thenaldehydes (44), the majority of the necessary starting materials were readily available. Consequently, the Reformatsky reaction was studied with these compounds. With the a-bromoesters the reaction was successfully carried out with four of the thenaldehydes and 2-acetothienone. The nature of the product seemed to depend on the degree of branching of the bromoester. In only one case, where ethyl bromoacetate was used, was a hydroxyester obtained. However, when the carbon atom adjacent to the carbethoxy group was substituted, the product usually contained a hydroxyl group. The dehydration by means of aqueous oxalic acid resulted in a nearly quantitative conversion to the unsaturated esters. 

More recently, Concellon has reported a stereoselective method for the formation of ( )-a,p-unsaturated esters that exploits a Sml2 Reformatsky reaction followed by an elimination.141 For example, ethyl dibromoacetate reacts with benzaldehyde in the presence of Sml2 to form samarium alkoxide 126, which is reduced further to give a second Sm(III) enolate 127. Elimination then affords ( )-a,p-unsaturated ester 128 in good yield (Scheme 5.90).141... 

The reaction has been studied by many workers. A review (447) covers the literature on this subject up to and including 1960, and the present work covers the years 1961-1972. This type of reaction with y-halo-a,j3-unsaturated esters is included in the reviews on the Reformatsky reaction. 

Some 16-substituted cardenolides have also been prepared.16) -Methyl-3/ -acetoxy-17a-pregnan-20-one (514) was converted into the unsaturated ester (515) by a Reformatsky reaction followed by dehydration. Selenium dioxide oxidation then gave the 16)S-methyl-17a-cardenolide (516). In the same way, 16a-cyano-3/3-acetoxy-17/l-pregnan-20-one (517) was transformed to the 16a-cyano-17)S-cardenolide (518). Failure to achieve the Reformatsky reaction on (519) was explained as a result of steric interference by the 16a-methyl group. 

The ketone (XXVI) was condensed with ethyl bromoacetate in a Reformatsky reaction, and the resulting unsaturated ester (XXXIV) was catalytically reduced and then saponified to give the endo acid (XXXV). Its configuration follows from its mode of formation and is confirmed by its cyclization in the presence of trifiuoroacetic anhydride to the bridge ketone (XXXVI). 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

Similar condensations can be accomplished with other types of stabilized carbanions, e.g. sulfonyl anions, as illustrated by equation (81). The resulting sulfonyl lactone (228) eliminates sulfinic acid on treatment with p-TsOH to furnish the a,3-unsaturated system (229).Spirolactonization is the result of the Reformatsky reaction of ester (231) with cyclic ketones. In equation (82), this reaction is applied to the synthesis of the lysergic acid precursor (232), which is formed stereoselectively from (230). ... 

Reformatsky reaction The reaction of an a-bromoester in the presence of zinc with an aldehyde or ketone to give a 3-hydroxyester or if dehydration subsequently occurs, then an a,(3-unsaturated ester. 

In the follow-up detailed report, Hudlicky s group (53) also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bro-... 

An indication that the 14j8-hydroxyl is not essential for cardiotonic activity comes from the synthesis of 14-desoxy-14)8-uzarigenin. Lithium aluminium hydride reduction and acetylation of the 17 0 -epoxide obtained from the enol acetate (79) gave the 17/ -alcohol (80), which underwent a Serini-Logemann reaction to afford the 14 -pregnane (81). Reformatsky reaction with ethyl bromoacetate and dehydration gave the a -unsaturated ester (82), converted by selenium dioxide to 14-desoxy-14)8-uzarigenin (83). 

The Reformatsky reaction is the reaction of an a-halo ester with an aldehyde or ketone in the presence of zinc metal as shown in Scheme 1. The usual product of the reaction is a -hydroxy ester, which may be dehydrated in subsequent steps to give an unsaturated ester. A zinc ester enolate (1), the so-called Reformatsky reagent, is an intermediate in the reaction and the sequence is thus classified as an aldol condensation. Compared to the usual base-promoted aldol procedures, the distinguishing features of the Reformatsky reaction are the use of a metal-halogen redox reaction rather than an acid-base reaction to form the enolate, and the fact that the counterion of the enolate is zinc. 

Reformatsky reactions of a-trimethylsilyl esters have been used to obtain a,(3-unsaturated esters directly from carbonyl substrates in a Peterson-type alkenation,81 as shown in equation (40). 

An alternative strategy for this type of olefination is the Reformatsky reaction, which, when mediated by tri-n-butyl stibine, directly gives excellent yields of (E)-a,B-unsaturated esters with or... 

This reaction is basically an electrophilic substitution, followed by hydrolysis. The Reformatsky reaction, which follows, is an organometallic reaction which yields a B-hydroxy ester or acid. Upon heating, we get the corresponding a,B-unsaturated product ... 

There was no problem with selectivity in the second aldol reaction because the aldehyde is not enolizable. The Reformatsky reaction in this sequence illustrates the fact that, as you saw in Chapter 26, aldol-type reactions happen at the ester oxidation level as well, and you should equally look to disconnect P-hydroxy or a,P-unsaturated esters, acids, or nitriles in this way. Just remember to look for 1,3-relationships, convert the functional groups to oxygen-based ones, and disconnect them to d plus a synthons. 

The Reformatsky reaction is the zinc-mediated condensation of an a-haloester, usually the bromoester, with an aldehyde or ketone, to give a 3-hydroxyester, dehydration of which affords an a,P-unsaturated ester as a mixture of (E)- and fZ>isomers [24]. It should be noted that a-halonitriles [25] and a-halosulphones [26] also participate in the Reformatsky reaction. The condensation is usually effected by adding a solution of the bromoester and the aldehyde or ketone to a suspension of zinc in a suitable solvent. The Reformatsky reaction has been conducted under sonication conditions [27] and by a continuous flow method [28]. 

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