The Reformatsky reaction

The application of this reaction to 17-keto steroids has not been studied extensively, probably because of the large number of steps required to transform the primary products to useful intermediates. 

The reaction of ethyl a-bromoacetate with 17-keto steroids such as estrone methyl ether or dehydroepiandrosterone acetate under standard Reformatsky conditions is stereospecific, producing the 17 -ol in up to 80% yields. Ethyl a-bromopropionate reacts similarly but the yields are somewhat lower. 

17a-Pregn-5-ene-3j5,17j5,21-triol and Ethyl 3j5-Acetoxy-17)5-hydroxy-17a-pregn S-en-ll-oate Ethyl bromoacetate (10 g) is added as quickly as the reaction permits to a stirred mixture of 3jS-hydroxyandrost-5-en-17-one acetate 

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The Reformatsky Reaction consists of the interaction of an ester of an a-halogeno-acid with an aldehyde, a ketone or another ester in the presence of zinc. For example, if a mixture of ethyl bromoacetate and benzaldehyde is heated with zinc, the latter undoubtedly first combines with the ethyl bromoacetate to form a Grignard-like reagent (reaction A), which then adds on to the benzaldehyde Just as a Grignard reagent would do (reaction B). The complex so formed, on acidification gives ethyl p-phenyl-p-hydroxy-propionate (reaction C). Note that reaction A could not satisfactorily be carried out using... 

This preparation illustrates the Reformatsky reaction, which consists in the interaction of a carbonyl compound, an a-halogen ester (e.g., ethyl bromo-acetate) and zinc In the presence of ether or benzene, followed by hydrolysis. 

This compound permits the introduction (in moderate yield) of a four carbon atom chain at the site of the carbonyl group by the use of the Reformatsky reaction (compare Section VI,8) ... 

By analogy with the Reformatsky reaction, the zinc derivative of a p-bromoester would do ... 

Conversion of androstans to pregnanes via the Reformatsky Reaction 17a-pregn-5-ene-3/3,17/3,21-triol and ethyl 3/3-acetoxy-17/3-hy droxy-17a-pregn-5-en-21-oate, 139... 

Bromination of the methyl group of (249) with A -bromosuccinimide, followed by reaction with excess secondary amine gave (250) which shows combined analgesic and antitussive properties. The Reformatsky reaction has also been used for the preparation of 2-amino-ethyl 3,3-diaryl-3-hydroxypropanates (251) as well as their dehydration products. The propene amides (252) have also been prepared for pharmacological evaluation. In l-methyl-3-bis (2-thienyl)-... 

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. 

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

Kitazume and Kasai [55] have investigated the Reformatsky reaction in three ionic liquids. This reaction involves treatment of an a-bromo ester with zinc to give an a-zinc bromide ester, which in turn reacts with an aldehyde to give an addition product. An example is given in Scheme 5.1-26. Moderate to good yields (45-95 %) were obtained in ionic liquids such as [EDBU][OTf] for the reactions between ethyl bro-moacetate or ethyl bromodifluoroacetate and benzaldehyde [55]. 

Similar ratios are obtained from the Reformatsky reaction of methyl bromoacetate28. The predominant formation of the. tyn-isomers is in accordance with Cram s rule1 or with the Felkin-Anh model2. 

The complexation of achiral metal enolates by chiral additives, e.g., solvents or complexing agents could, in principle, lead to reagent-induced stereoselectivity. In an early investigation, the Reformatsky reaction of ethyl bromoacetate was performed in the presence of the bidentate ligand (—)-sparteine20. The enantioselectivity of this reaction varies over a wide range and depends on the carbonyl Compound, as shown with bcnzaldehyde and acetophenone. 

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. 

This result is similar to that obtained in the Reformatsky reaction (16-31), but this is more general since no ester or other group is required to be a to the halogen. Another important advantage of the Wittig reaction is that the position of the new double bond is always certain, in contrast to the result in the Reformatsky reaction and in most of the base-catalyzed condensations (16-38-16-46). Examples of this are given below. 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

The Reformatsky reaction is related to both organometallic and aldol addition reactions and probably involves a cyclic TS. The Reformatsky reagent from /-butyl bromoacetate crystallizes as a dimer having both O—Zn (enolate-like) and C—Zn (organometallic-like) bonds (see Figure 7.5).165... 

Scheme 7.5 gives some examples of the Reformatsky reaction. Zinc enolates prepared from a-haloketones can be used as nucleophiles in mixed aldol condensations (see Section 2.1.3). Entry 7 is an example. This type of reaction can be conducted in the presence of the Lewis acid diethylaluminum chloride, in which case addition occurs at -20° C.171... 

Two further methods for the preparation of p-ketoesters consist of the Reformatsky reaction of pyrazolides[67] (a) and the magnesium bromide-induced Claisen condensation of pyrazolides[68] (b). 

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... 

Highly reactive zinc can be prepared by reduction of anhydrous ZnC with potassium/THF or sodium/DME(l 7,29). This zinc has been shown to undergo rapid oxidative additions with alkyl bromides to produce near quantitative yields of the corresponding dialkylzinc. It also underwent oxidative addition with phenyl iodide and bromide. Moreover, the zinc was found to be useful in the Reformatsky reaction. Reactions could be carried out in diethyl ether at room temperature to generate near quantitative yields of the 3-hydroxyester. 

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